Pharmaceutical compositions of dispersions of drugs and neutral polymers

ABSTRACT

In one aspect, pharmaceutical compositions comprising dispersions of an acid-sensitive drug and a neutral dispersion polymer are disclosed. The acid-sensitive drug has improved chemical stability relative to dispersions of the drug and acidic polymers. In another aspect, pharmaceutical compositions of low-solubility drugs and amphiphilic, hydroxy-functional vinyl copolymers are disclosed.

[0001] This application claims the benefit of priority of provisionalPatent Application Serial No. 60/300,255 filed Jun. 22, 2001, which isincorporated herein by reference in its entirety for all purposes.

BACKGROUND OF THE INVENTION

[0002] This invention relates to pharmaceutical compositions comprisedof amorphous dispersions of drugs and neutral polymers that provideeither improved chemical stability, concentration-enhancement, or bothimproved chemical stability and concentration-enhancement.

[0003] It is sometimes desired to form a solid amorphous dispersion of adrug and a polymer. One reason for forming dispersions is that theaqueous concentration of a poorly soluble drug may be improved byforming an amorphous dispersion of the drug and a polymer. For example,Curatolo, et al., EP 0 901 786 A2 disclose forming pharmaceutical spraydried dispersions of sparingly soluble drugs and the polymerhydroxypropyl methyl cellulose acetate succinate. The spray drieddispersions disclosed in Curatolo et al. provide superior aqueousconcentration relative to dispersions formed from other methods andrelative to the crystalline drug alone.

[0004] Similarly, others have recognized the enhancement in aqueousconcentration afforded by dispersing a drug in a polymer. Nakamichi, etal., U.S. Pat. No. 5,456,923 disclose solid dispersions formed bytwin-screw extrusion of low solubility drugs and various polymers.

[0005] Another reason for forming an amorphous dispersion is that it maybe desired to use a particular process for forming a pharmaceuticalcomposition, such as a spray-coating or wet granulation process whichresults in the formation of amorphous drug, in whole or in part, ratherthan pure crystalline drug. Thus, amorphous dispersions may be formed ofdrugs which are not low-solubility drugs.

[0006] However, regardless of whether the drug is poorly soluble, theinventors have determined that for some drug and polymer dispersions,the drug is not chemically stable in the dispersion. In particular, theinventors have observed that for dispersions containing certain drugsand polymers, the drug degrades in the dispersion over time, resultingin a loss of potency for the composition. The inventors have found thisproblem to arise especially for acid-sensitive drugs.

[0007] Drug degradation within the dispersion is a particular problemfor low-solubility, acid-sensitive drugs, since the increase in aqueousconcentration of the drug provided by the dispersion is offset bydecreasing drug purity. In general, the greatestconcentration-enhancement is often observed through the use of acidicdispersion polymers, especially acidic, cellulosic enteric polymers.However, the use of such acidic polymers within the dispersion isprecluded due to the acid-sensitive nature of the drug.

[0008] Accordingly, there is still a need for pharmaceuticalcompositions of dispersions containing acid-sensitive drugs that arechemically stable over time. Likewise, there is also a continuing needto provide concentration-enhancement for low-solubility drugs.

BRIEF SUMMARY OF INVENTION

[0009] The present invention relates to, in a first aspect,pharmaceutical compositions comprising a solid amorphous dispersion ofan acid-sensitive drug and a neutral dispersion polymer, wherein saidcomposition provides improved chemical stability relative to a controlacidic dispersion comprising an equivalent quantity of said drug and anacidic polymer.

[0010] In a preferred embodiment, the acid-sensitive drug has one ormore functional groups selected from the group consisting of sulfonylureas, hydroxamic acids, hydroxy amides, carbamates, acetals, hydroxyureas, esters, and amides.

[0011] In another preferred embodiment, the acid-sensitive drug whenpresent in a control acidic dispersion and stored for a period of sixmonths at 40° C. and 75% relative humidity has a degree of degradationof at least 0.01%, preferably at least 0.1%.

[0012] In another preferred embodiment, the drug isquinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-3-fluorobenzyl-2(S),7-dihydroxy-7-methyl-octyl]amide;quinoxaline-2-carboxylic acid[1-benzyl-4-(4,4-difluoro-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide;quinoxaline-2-carboxylic acid[1-benzyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide;(+)-N-{3-[3-(4-fluorophenoxy)phenyl]-2-cyclopenten-1-yl}-N-hydroxyurea;omeprazole; etoposide; famotidine; erythromycin; quinapril;lansoprazole; or progabide.

[0013] In another preferred embodiment, the drug in said composition hasa relative degree of improvement in chemical stability of at least 1.25,preferably at least 3, more preferably at least 10. Preferably, drug insaid composition has a relative degree of improvement in chemicalstability of at least 1.25 when stored at 40° C. and 75% relativehumidity for a period of six months.

[0014] In another preferred embodiment, the dispersion polymer isionizable, non-ionizable, cellulosic, or non-cellulosic. Preferredcellulosic dispersion polymers include hydroxypropyl methyl celluloseacetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl methyl cellulose, hydroxyethyl celluloseacetate, and hydroxyethyl ethyl cellulose. Preferred non-cellulosicdispersion polymers include vinyl polymers and copolymers having one ormore substituents comprising hydroxyl-containing repeat units,alkylacyloxy-containing repeat units, or cyclicamido-containing repeatunits; polyvinyl alcohols that have at least a portion of their repeatunits in the unhydrolyzed form; polyvinyl alcohol polyvinyl acetatecopolymers; polyethylene glycol, polyethylene glycol polypropyleneglycol copolymers, polyvinyl pyrrolidone; polyethylene polyvinyl alcoholcopolymers, and polyoxyethylene-polyoxypropylene block copolymers.Preferrably, the non-cellulosic dispersion polymer comprising a vinylcopolymer having: (1) hydroxyl-containing repeat units; and (2)hydrophobic repeat units.

[0015] In another preferred embodiment, the acid-sensitive drug is alsoa low-solubility drug and said dispersion polymer isconcentration-enhancing. Preferably, the drug has a minimum solubilityin aqueous solution in the absence of said dispersion polymer of lessthan 1 mg/mL at any pH of from about 1 to about 8, more preferably theminimum aqueous solubility is less than 0.01 mg/mL.

[0016] In another preferred embodiment, the drug has adose-to-aqueous-solubility ratio of at least 10 mL.

[0017] In yet another preferred embodiment, the dispersion polymer ispresent in an amount sufficient to provide a maximum concentration ofsaid acid-sensitive drug in a use environment that is at least1.25-fold, preferably at least 2-fold, that provided by a second controlcomposition comprising an equivalent quantity of said acid-sensitivedrug and free from said dispersion polymer.

[0018] In another preferred embodiment, the dispersion polymer ispresent in a sufficient amount so that said dispersion provides in a useenvironment an area under the concentration versus time curve for anyperiod of at least 90 minutes between the time of introduction into theuse environment and about 270 minutes following introduction to the useenvironment that is at least 1.25-fold, preferably at least 2-fold, thatprovided by a second control composition comprising an equivalentquantity of said acid-sensitive drug and free from said dispersionpolymer.

[0019] In another preferred embodiment, the dispersion polymer ispresent in a sufficient amount so that said dispersion provides arelative bioavailability that is at least 1.25, preferably at least 2,relative to a second control composition comprising an equivalentquantity of said acid-sensitive drug and free from said polymer.

[0020] In yet another preferred embodiment, the drug is base-sensitiveand said dispersion polymer is non-ionizable.

[0021] In another preferred embodiment, the dispersion comprising abuffer. Preferred buffers include sodium acetate, ammonium acetate,sodium carbonate, sodium bicarbonate, disodium hydrogen phosphate andtrisodium phosphate. Preferably, the buffer comprises at least 10 wt %of said dispersion.

[0022] In another preferred embodiment, the dispersion has a pH fromabout 6 to about 10. Preferably, the composition comprising a base andthe dispersion has a pH of from about 6 to about 10.

[0023] In still another preferred embodiment, the acid-sensitive drug isa low-solubility drug and the composition comprising a second polymer,said dispersion is free from at least a portion of said second polymer,and said second polymer is concentration-enhancing. Preferably, thesecond polymer has at least one hydrophobic portion and at least onehydrophilic portion. More preferably, the second polymer is acellulosic, ionizable polymer, comprising hydroxypropyl methyl celluloseacetate succinate, hydroxypropyl methyl cellulose succinate,hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulosesuccinate, hydroxyethyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, hydroxyethyl methyl cellulose acetatesuccinate, hydroxyethyl methyl cellulose acetate phthalate, carboxyethylcellulose, carboxymethyl cellulose, cellulose acetate phthalate, methylcellulose acetate phthalate, ethyl cellulose acetate phthalate,hydroxypropyl cellulose acetate phthalate, hydroxypropyl methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalatesuccinate, hydroxypropyl methyl cellulose acetate succinate phthalate,hydroxypropyl methyl cellulose succinate phthalate, cellulose propionatephthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetatetrimellitate, methyl cellulose acetate trimellitate, ethyl celluloseacetate trimellitate, hydroxypropyl cellulose acetate trimellitate,hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate succinate, cellulose propionatetrimellitate, cellulose butyrate trimellitate, cellulose acetateterephthalate, cellulose acetate isophthalate, cellulose acetatepyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropylsalicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate,hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acidcellulose acetate, ethyl nicotinic acid cellulose acetate, and ethylpicolinic acid cellulose acetate. Other more preferable second polymersare non-ionizable cellulosic polymers comprising hydroxypropyl methylcellulose acetate, hydroxypropyl methyl cellulose, hydroxypropylcellulose, methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethylcellulose acetate, and hydroxyethyl ethyl cellulose. Still other morepreferably second polymers are ionizable, non-cellulosic polymerscomprising carboxylic acid functionalized polymethacrylates, carboxylicacid functionalized polyacrylates, amine-functionalized polyacrylates,amine-fuctinoalized polymethacrylates, proteins, and carboxylic acidfunctionalized starches.

[0024] Yet other more preferable second polymers are non-ionizable,non-cellulosic polymers comprising vinyl polymers and copolymers havingone or more substituents such as hydroxyl-containing repeat units,alkylacyloxy-containing repeat units, or cyclicamido-containing repeatunits; polyvinyl alcohols that have at least a portion of their repeatunits in the unhydrolyzed form; polyvinyl alcohol polyvinyl acetatecopolymers; polyethylene glycol, polyethylene glycol polypropyleneglycol copolymers, polyvinyl pyrrolidone polyethylene polyvinyl alcoholcopolymers, and polyoxyethylene-polyoxypropylene block copolymers.Within these vinyl copolymers, preferably the second polymer has (1)hydroxyl-containing repeat units; and (2) hydrophobic repeat units.

[0025] In another preferred embodiment, the drug in said composition hasa relative degree of improvement in chemical stability of at least 1.25,preferably at least 3.

[0026] In another preferred embodiment, the dispersion is mixed withsaid second polymer. Another preferred embodiment, the dispersion andsaid second polymer occupy separate regions of said composition.

[0027] In still another preferred embodiment, the second polymer ispresent in an amount sufficient to provide a maximum concentration ofsaid acid-sensitive drug in a use environment that is at least1.25-fold, preferably at least 2-fold, that of a control compositioncomprising an equivalent quantity of said dispersion and free from saidsecond polymer.

[0028] In another preferred embodiment, the second polymer is present ina sufficient amount so that said composition provides in a useenvironment an area under the concentration versus time curve for anyperiod of at least 90 minutes between the time of introduction into theuse environment and about 270 minutes following introduction to the useenvironment that is at least 1.25-fold, preferably at least 2-fold, thatof a control composition comprising an equivalent quantity of saiddispersion and free from said second polymer.

[0029] In another preferred embodiment, the second polymer is present ina sufficient amount so that said composition provides a relativebioavailability that is at least 1.25, preferably at least 2, relativeto a control composition comprising an equivalent quantity of saiddispersion and free from said second polymer.

[0030] A second aspect of the present invention relates to methods fortreating a condition in an animal comprising by administering to ananimal in need of such treatment a therapeutic amount of theabove-described composition.

[0031] A third aspect of the present invention relates to methods ofadministering a pharmaceutical composition comprising co-administeringto a patient: (a) a solid amorphous dispersion comprising anacid-sensitive drug and a neutral polymer; and (b) a second polymer,wherein said dispersion is substantially free from said second polymerand said second polymer is concentration-enhancing.

[0032] In one preferred embodiment, the second polymer is cellulosic,such as hydroxypropyl methyl cellulose acetate succinate, celluloseacetate phthalate, hydroxypropyl methyl cellulose phthalate, methylcellulose acetate phthalate, cellulose acetate trimellitate,hydroxypropyl cellulose acetate phthalate, cellulose acetateterephthalate and cellulose acetate isophthalate.

[0033] In another preferred embodiment, the dispersion is administeredseparately from said second polymer. Preferably, the dispersion and saidsecond polymer are administered at about the same time.

[0034] A fourth aspect of the present invention relates topharmaceutical compositions that a solid amorphous dispersion of alow-solubility drug and a neutral dispersion polymer, wherein saidneutral dispersion polymer comprising a vinyl copolymer havinghydrophilic hydroxyl-containing repeat units and hydrophobic repeatunits.

[0035] In one preferred embodiment, the hydrophobic repeat units includeester-linked alkylate or arylate substituents. More preferably, thehydrophobic repeat unit is an alkylate such as acetate, propionate, andbutyrate. More preferably, the hydrophobic repeat units comprise theacetylated form of the hydroxyl-containing repeat units. Preferably, theacetylated form of the hydroxyl-containing repeat units comprise 0.5 to30% of the repeat units of the polymer.

[0036] In another preferred embodiment, the hydroxyl-containing repeatunit is vinyl alcohol.

[0037] In another preferred embodiment, the dispersion polymer is avinyl alcohol/vinyl acetate copolymer. Preferably, from about 0.5% toabout 30% of the repeat units of said polymer are vinyl acetate.

[0038] A fifth aspect of the present invention relates to pharmaceuticalcompositions that include a solid amorphous dispersion comprising alow-solubility drug, a neutral dispersion polymer, and an excipient suchas a base or a buffer.

[0039] In a preferred embodiment, the neutral dispersion polymer isconcentration enhancing. Preferred neutral dispersion polymers arepresent in an amount sufficient to provide a maximum concentration ofsaid low-solubility drug in a use environment that is at least1.25-fold, preferably at least 2-fold, that provided by a second controlcomposition comprising an equivalent quantity of said low-solubilitydrug and free from a concentration-enhancing polymer.

[0040] In another preferred embodiment, the neutral dispersion polymeris present in a sufficient amount so that said composition, whenintroduced to a use environment, provides an area under theconcentration-versus time curve for any period of at least 90 minutesbetween the time of introduction to the use environment and about 270minutes following introduction to the use environment that is at least1.25-fold, preferably at least 2-fold, that of a second controlcomposition comprising an equivalent quantity of said low-solubilitydrug and free from a concentration-enhancing polymer.

[0041] In another preferred embodiment, the neutral dispersion polymeris present in a sufficient amount so that said composition provides arelative bioavailability that is at least 1.25, preferably at least 2,relative to a second control composition comprising an equivalentquantity of said low-solubility drug and free from aconcentration-enhancing polymer.

[0042] In another preferred embodiment, the drug in said composition hasa relative degree of improvement in chemical stability of at least 1.25.

[0043] In yet another preferred embodiment, the composition providesimproved chemical stability relative to a control composition, whereinsaid control comprising an equivalent quantity of a dispersion of saiddrug and said neutral dispersion polymer but free from said base andsaid buffer.

[0044] As described more fully below, the term “use environment” mayrefer to the in vivo environment of the gastrointestinal (GI) tract ofan animal, particularly a human, or the in vitro environment of a testsolution, such as phosphate buffered saline (PBS) or model fastedduodenal (MFD) solution.

[0045] The composition may be dosed in a variety of dosage forms,including both immediate release and controlled release dosage forms,the latter including both delayed and sustained release forms. Thecomposition may include blends of polymers.

[0046] The various aspects of the present invention provide one or moreof the following advantages. For those embodiments comprising anacid-sensitive drug, the inventors have recognized that a problem withforming dispersions of acid-sensitive drugs is that for somedispersions, the drug does not remain chemically stable in thedispersion over time. The inventors have found that acid-sensitive drugsdispersed in an acidic polymer, such as hydroxypropyl methyl celluloseacetate succinate (which has carboxylic acid functional groups), have atendency to chemically degrade over time. It is believed that thepresence of acidic ionic groups on the acidic polymer may eithercatalyze degradation of the drug or react directly with the drug. In anyevent, regardless of the particular degradation mechanism, the inventorshave substantially reduced, if not eliminated the problem of drugdegradation, by forming dispersions using neutral polymers, i.e.polymers that do not include acidic functional groups. Thus, the presentinvention is able to realize the advantages of forming dispersions ofacid-sensitive drugs by improving the chemical stability of theacid-sensitive drug in the dispersion.

[0047] In addition, the invention in some embodiments further providesenhanced aqueous concentration and bioavailability for low-solubilitydrugs while at the same time minimizing the loss in potency andgeneration of impurities in the composition resulting from reaction ordegradation of the drug when in the presence of an acidic species, suchas an acidic dispersion polymer.

[0048] For those aspects comprising neutral vinyl copolymers of thepresent invention having hydroxyl-containing repeat units andhydrophobic repeat units, the compositions provide surprisinglyeffective concentration-enhancement. The polymers may be used with anylow-solubility drug to improve the concentration of the drug in a useenvironment.

[0049] The foregoing and other objectives, features, and advantages ofthe invention will be more readily understood upon consideration of thefollowing detailed description of the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0050] The pharmaceutical compositions of the present invention comprisesolid amorphous dispersions of a drug and a neutral dispersion polymer.The present invention finds utility anytime it is desired to improveeither the chemical stability of an acid-sensitive drug, to improve theconcentration or bioavailability of a low-solubility drug, or both. Inone embodiment of the invention, the dispersions of the presentinvention improve the chemical stability of acid-sensitive drugs. Thus,the dispersions may be used to prevent degradation of the drug due tointeractions with dispersion polymers, acidic dispersion species, orother acidic excipients present in the composition. In anotherembodiment, the dispersions improve the concentration or bioavailabilityof a low-solubility drug. Suitable acid-sensitive drugs, low-solubilitydrugs, neutral polymers and methods for making the dispersions arediscussed in more detail below.

ACID-SENSITIVE DRUGS

[0051] The term “drug” is conventional, denoting a compound havingbeneficial prophylactic and/or therapeutic properties when administeredto an animal, especially humans. In one embodiment of the invention, thedrug is an acid-sensitive drug, meaning that the drug either chemicallyreacts with or otherwise degrades in the presence of acidic species.Acid-sensitive drugs often include functional groups which are reactiveunder acidic conditions, such as sulfonyl ureas, hydroxamic acids,hydroxy amides, carbamates, acetals, hydroxy ureas, esters, and amides.Drugs which include such functional groups may be prone to reactionssuch as hydrolysis, lactonization, or transesterification in thepresence of acidic species.

[0052] Acid-sensitive drugs may be identified experimentally bydetermining whether the drug chemically reacts or degrades whendispersed in an acidic polymer. In particular, as used herein, the term“acid-sensitive drug” refers to a drug which, when dispersed in a“control acidic dispersion,” degrades when stored under controlled agingconditions either for long storage times at ambient storage conditionsor for short storage times under elevated temperature and relativehumidity conditions.

[0053] The “control acidic dispersion” used to determine whether a drugis acid-sensitive is a dispersion of the drug and a pharmaceuticallyacceptable acidic polymer. A convenient pharmaceutically acceptableacidic polymer for use as the acidic dispersion polymer is the HF gradeof hydroxypropyl methyl cellulose acetate succinate (HPMCAS), which isan acidic, or so-called enteric polymer having carboxylic acidfunctional groups, and a pK_(a) of about 5. The HPMCAS in the controlacidic dispersion should have a minimum degree of substitution ofsuccinate groups (O(CO)CH₂CH₂(CO)OH) of at least 4 wt % (or at leastabout 100 milliequivalents of carboxylic acid functional groups per moleof polymer). Alternatively, other acidic polymers which are at least asacidic as the HF grade of HPMCAS may be used, such as hydroxypropylmethyl cellulose acetate phthalate (HPMCP) or cellulose acetatephthalate (CAP). As with HPMCAS, such polymers should have at leastabout 100 milliequivalents of carboxylic acid functional groups per moleof polymer. The amount of acidic polymer present in the control acidicdispersion may vary, but should comprise at least 50 wt % or more of thecontrol acidic dispersion. A drug is an acid-sensitive drug if it meetsthe drug degradation criteria described below in at least one controlacidic dispersion comprised of 25 wt % drug and 75 wt % of thedispersion polymer HPMCAS, HPMCP or CAP.

[0054] In general, drug degradation may be measured using anyconventional method for measuring the purity or potency of drug in apharmaceutical composition. For example, the amount of active drugpresent in a dispersion may be measured initially using high-performanceliquid chromatography (HPLC) or any other analytical technique wellknown in the art. Alternatively, the amount of drug initially presentmay be calculated from the amount of drug present in the dispersionformulation. The potency of the dispersion may then be measured afterstorage at controlled temperature and humidity conditions for anappropriate period of time. A decrease in potency indicates that achemical reaction has occurred, leading to a decrease in the amount ofactive drug present in the dispersion, and is an indication of poorchemical stability.

[0055] An alternative method used to evaluate chemical stability is toanalyze the rate of increase in the amount of drug degradant(s) in thedispersion, which would indicate reaction of the drug to form thedegradant(s). An HPLC or other analytical technique may be used todetermine the concentration of drug degradant(s) in a dispersion. Theamount of the degradant(s) is measured before and after storage undercontrolled aging conditions. The amount of increase in the drugdegradant(s) may be used to determine the amount of decrease in “percentdrug purity.” The “percent drug purity” is defined as 100 times thetotal amount of drug present divided by the total amount of druginitially present. Thus, a percent drug purity at a given time may becalculated by the formula${{wt}\quad \% \quad {drug}\quad {purity}} = {\left( \frac{{total}\quad {{amt}.\quad {of}}\quad {drug}\quad {present}}{{total}\quad {{amt}.\quad {of}}\quad {drug}\quad {{init}.\quad {present}}} \right)*100}$

[0056] When the drug purity is calculated from the total amount ofimpurities, “percent drug purity” may be calculated by assuming that the“total amount of drug initially present,” given in wt %, is equal to 100wt % minus the wt % of total initial impurities, and that “total amountof drug present” is equal to 100 wt % minus the wt % of total impuritiesafter storage, that is, at some later time. This method is equivalent tocalculating “percent drug purity” by the formula${{wt}\quad \% \quad {drug}\quad {purity}} = {\left\lbrack {1 - \left( \frac{{total}\quad {{amt}.\quad {of}}\quad {impurities}}{{total}\quad {{amt}.\quad {of}}\quad {drug}\quad {{init}.\quad {present}}} \right)} \right\rbrack*100}$

[0057] The rate at which drug degradation occurs is generally dependenton the storage conditions. The drug, when formulated as a composition ofthe present invention, should be stable at ambient temperature andhumidity conditions (e.g., relative humidities of 20% to 60%) for longperiods of time, such as months or years. However, to expedite testing,the storage conditions may employ elevated temperature and/or humidityto simulate longer storage times at ambient conditions. The storage timemay vary from a few days to weeks or months, depending on the reactivityof the drug and the storage conditions.

[0058] A “degree of degradation” of drug following storage may bedetermined by subtracting the final percent drug purity (eitherdetermined by measuring the decrease in drug present or an increase inthe amount of drug degradants present) from the initial percent drugpurity. For example, for a dispersion initially containing 100 mg drug,and no measurable impurities, the initial percent drug purity is 100 wt%. If, after storage, the amount of drug in the dispersion decreases to95 mg, the final percent drug purity would be 95 wt % and the “degree ofdegradation” is 5 wt % (100 wt %−95 wt %). Alternatively, if 100 mg ofdrug substance were found to initially have 1 mg of impurities present,it would have an initial “percent drug purity” of 99 wt %. If, afterstorage, the total impurities present had increased to 6 wt %, the finalpercent drug purity would be 94 wt % and the “degree of degradation”would be 5 wt % (99 wt %−94 wt %).

[0059] Alternatively, “degree of degradation” can be determined bysubtracting from the amount of one or more specific degradants initiallypresent from the amount of that specific drug degradant present afterstorage. Such a measure is useful where there are several drugdegradants, of which only one (or a few) is of concern. The degree ofdegradation may be calculated on the basis of only those degradants thatare of concern, rather than all of the degradant. For example, if a druginitially contained a specific degradant at a concentration of 1 wt %and after storage the concentration of that degradant was 6 wt %, thedegree of degradation would be 5 wt % (6 wt %−1 wt %).

[0060] Returning now to the determination of an acid-sensitive drug, asused herein an “acid-sensitive” drug is one in which the degree ofdegradation of the drug in a control acidic dispersion (as definedabove) is at least 0.01 wt % in a six month period at 40° C. and 75%relative humidity (RH), or alternatively, in which the degree ofdegradation is at least 0.01 wt % in a one year period at 30° C. at 60%RH, or as defined below with respect to degradation of drug in an acidicaqueous solution. These storage conditions are conventional andwell-known in the art, and are the ICH recommendations for storageconditions to be used to evaluate the stability of a drug after storagefor two years at ambient temperature and humidity. A relative degree ofimprovement may become apparent within a shorter time, such as three tofive days, and shorter storage times may be used for some veryacid-sensitive drugs.

[0061] The need for the present invention will generally be greater whenthe drug's reactivity with or sensitivity to acidic species increases.Dispersions of the present invention are preferred for acid-sensitivedrugs having a degree of degradation that is greater than the minimumlevel when in the presence of an acidic dispersion polymer. Thus, thedispersions of the present invention are preferred for “veryacid-sensitive drugs.” Very acid-sensitive drugs are those which, whendispersed in a control acidic dispersion, have a degree of degradationof at least 0.1 wt % when stored at 40° C./75% RH for six months.

[0062] The dispersions are even more preferred for drugs which have adegree of degradation of at least 1 wt %, and are most preferred fordrugs which have a degree of degradation of at least 5.0 wt % whenstored at 40° C./75% RH for six months.

[0063] In addition, the acid-sensitive drug when present in the controlacidic dispersion degrades at a rate that is greater than the rate atwhich pure drug in the amorphous form, or if the amorphous form isphysically unstable, the crystalline form, degrades. A relative degreeof degradation of the drug in a control acidic dispersion to the pureform of the drug may be determined by taking the ratio of the degree ofdegradation of the drug in the control acidic dispersion and the degreeof degradation of the pure form of the drug under the same storageconditions for the same storage time period. For example, where thedegree of degradation of the drug in the control acidic dispersion is 5wt % and the degree of degradation of the pure amorphous form of thedrug is 0.1 wt %, the relative degree of degradation of the drug in thecontrol acidic dispersion to the pure form of the drug is 50 (5 wt %/0.1wt %). An acid-sensitive drug is one in which the relative degree ofdegradation of the drug in the control composition to the pure form ofthe drug is at least 2. The invention finds increasing utility as therelative degree of degradation increases above this minimum level. Thus,the invention is preferred for drugs having a relative degree ofdegradation of about 3 or more, and more preferred for drugs having arelative degree of degradation of about 5 or more.

[0064] Alternatively, another test to determine whether a drug is anacid sensitive drug as used herein is to administer the drug to anacidic aqueous solution and plot drug concentration versus time. Theacidic solution should have a pH of from 1-4. Drugs which are acidsensitive are those for which the drug concentration decreases by atleast 1% within 24 hours of administration of the drug to the acidicsolution. If the drug concentration changes by 1% in the 6-24 hour timeperiod, then the drug is “slightly acid-sensitive.” If the drugconcentration changes by 1% in the 1-6 hour time period, then the drugis “moderately acid-sensitive.” If the drug concentration changes by 1%in less than 1 hour, then the drug is “highly acid-sensitive.” Thepresent invention finds increasing utility for drugs which are slightlyacid-sensitive, moderately acid-sensitive and highly acid-sensitive.

[0065] Specific examples of acid-sensitive drugs deliverable by theinvention are set forth below, by way of example only. Each named drugshould be understood to include the neutral form of the drug,pharmaceutically acceptable salts, and prodrugs. Examples ofacid-sensitive drugs include quinoxaline-2-carboxylic acid[4(R)-carbamoyl-1(S)-3-fluorobenzyl-2(S),7-dihydroxy-7-methyl-octyl]amide;quinoxaline-2-carboxylic acid[1-benzyl-4-(4,4-difluoro-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide; quinoxaline-2-carboxylic acid[1-benzyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide;(+)-N-{3-[3-(4-fluorophenoxy)phenyl]-2-cyclopenten-1-yl}-N-hydroxyurea;omeprazole; etoposide; famotidine; erythromycin; quinapril;lansoprazole; and progabide.

LOW-SOLUBILITY DRUGS

[0066] In another embodiment of the invention, the drug is a“low-solubility drug,” meaning that the drug may be either“substantially water-insoluble,” which means that the drug has a minimumaqueous solubility at physiologically relevant pH (e.g., pH 1-8) of lessthan 0.01 mg/mL, “sparingly water-soluble,” that is, has an aqueoussolubility up to about 1 to 2 mg/mL, or even low to moderateaqueous-solubility, having an aqueous-solubility from about 1 mg/mL toas high as about 20 to 40 mg/mL. In general, it may be said that thedrug has a dose-to-aqueous solubility ratio greater than 10 mL, and moretypically greater than 100 mL, where the drug solubility (mg/mL) is theminimum value observed in any physiologically relevant aqueous solution(e.g., those with pH values between 1 and 8) including USP simulatedgastric and intestinal buffers, and dose is in mg. Thedose-to-aqueous-solubility-ratio may be determined by simply dividingthe dose (in mg) by the aqueous solubility (in mg/mL).

[0067] Preferred classes of drugs include, but are not limited to,antihypertensives, antianxiety agents, anticlotting agents,anticonvulsants, blood glucose-lowering agents, decongestants,antihistamines, antitussives, antineoplastics, beta blockers,anti-inflammatories, antipsychotic agents, cognitive enhancers,anti-atherosclerotic agents, cholesterol-reducing agents, antiobesityagents, autoimmune disorder agents, anti-impotence agents, antibacterialand antifungal agents, hypnotic agents, anti-Parkinsonism agents,anti-Alzheimer's disease agents, antibiotics, anti-depressants, andantiviral agents, glycogen phosphorylase inhibitors, and cholesterolester transfer protein inhibitors.

[0068] Each named drug should be understood to include the neutral formof the drug, pharmaceutically acceptable salts, as well as prodrugs.Specific examples of antihypertensives include prazosin, nifedipine,amlodipine besylate, trimazosin and doxazosin; specific examples of ablood glucose-lowering agent are glipizide and chlorpropamide; aspecific example of an anti-impotence agent is sildenafil and sildenafilcitrate; specific examples of antineoplastics include chlorambucil,lomustine and echinomycin; a specific example of an imidazole-typeantineoplastic is tubulazole; a specific example of ananti-hypercholesterolemic is atorvastatin calcium; specific examples ofanxiolytics include hydroxyzine hydrochloride and doxepin hydrochloride;specific examples of anti-inflammatory agents include betamethasone,prednisolone, aspirin, piroxicam, valdecoxib, carprofen, celecoxib,flurbiprofen and(+)-N-{4-[3-(4-fluorophenoxy)phenoxy]-2-cyclopenten-1-yl}-N-hyroxyurea;a specific example of a barbiturate is phenobarbital; specific examplesof antivirals include acyclovir, nelfinavir, and virazole; specificexamples of vitamins/nutritional agents include retinol and vitamin E;specific examples of beta blockers include timolol and nadolol; aspecific example of an emetic is apomorphine; specific examples of adiuretic include chlorthalidone and spironolactone; a specific exampleof an anticoagulant is dicumarol; specific examples of cardiotonicsinclude digoxin and digitoxin; specific examples of androgens include17-methyltestosterone and testosterone; a specific example of a mineralcorticoid is desoxycorticosterone; a specific example of a steroidalhypnotic/anesthetic is alfaxalone; specific examples of anabolic agentsinclude fluoxymesterone and methanstenolone; specific examples ofantidepression agents include sulpiride,[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethylpropyl)-amine,3,5-dimethyl-4-(3′-pentoxy)-2-(2′,4′,6′-trimethylphenoxy)pyridine,pyroxidine, fluoxetine, paroxetine, venlafaxine and sertraline; specificexamples of antibiotics include carbenicillin indanylsodium,bacampicillin hydrochloride, troleandomycin, doxycyline hyclate,ampicillin and penicillin G; specific examples of anti-infectivesinclude benzalkonium chloride and chlorhexidine; specific examples ofcoronary vasodilators include nitroglycerin and mioflazine; a specificexample of a hypnotic is etomidate; specific examples of carbonicanhydrase inhibitors include acetazolamide and chlorzolamide; specificexamples of antifungals include econazole, terconazole, fluconazole,voriconazole, and griseofulvin; a specific example of an antiprotozoalis metronidazole; specific examples of anthelmintic agents includethiabendazole and oxfendazole and morantel; specific examples ofantihistamines include astemizole, levocabastine, cetirizine,decarboethoxyloratadine and cinnarizine; specific examples ofantipsychotics include ziprasidone, olanzepine, thiothixenehydrochloride, fluspirilene, risperidone and penfluridole; specificexamples of gastrointestinal agents include loperamide and cisapride;specific examples of serotonin antagonists include ketanserin andmianserin; a specific example of an anesthetic is lidocaine; a specificexample of a hypoglycemic agent is acetohexamide; a specific example ofan anti-emetic is dimenhydrinate; a specific example of an antibacterialis cotrimoxazole; a specific example of a dopaminergic agent is L-DOPA;specific examples of anti-Alzheimer's Disease agents are THA anddonepezil; a specific example of an anti-ulcer agent/H2 antagonist isfamotidine; specific examples of sedative/hypnotic agents includechlordiazepoxide and triazolam; a specific example of a vasodilator isalprostadil; a specific example of a platelet inhibitor is prostacyclin;specific examples of ACE inhibitor/antihypertensive agents includeenalaprilic acid and lisinopril; specific examples of tetracyclineantibiotics include oxytetracycline and minocycline; specific examplesof macrolide antibiotics include erythromycin, clarithromycin, andspiramycin; a specific example of an azalide antibiotic is azithromycin;specific examples of glycogen phosphorylase inhibitors include[R-(R*S*)]-5-chloro-N-[2-hydroxy-3-{methoxymethylamino}-3-oxo-1-(phenylmethyl)propyl-1H-indole-2-carboxamideand 5-chloro-1 H-indole-2-carboxylic acid[(1S)-benzyl-(2R)-hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-3-oxypropyl]amide;and specific examples of cholesterol ester transfer protein (CETP)inhibitors include[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester,[2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester,[2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

[0069] The invention is not limited by any particular structure or groupof CETP inhibitors. Rather, the invention has general applicability toCETP inhibitors as a class, the class tending to be composed ofcompounds having low solubility.

[0070] Compounds which may be the subject of the invention may be foundin a number of patents and published applications, including DE 19741400A1; DE 19741399 A1; WO 9914215 A1; WO 9914174; DE 19709125 A1; DE19704244 A1; DE 19704243 A1; EP 818448 A1; WO 9804528 A2; DE 19627431Al; DE 19627430 A1; DE 19627419 A1; EP 796846 A1; DE 19832159; DE818197; DE 19741051; WO 9941237 A1; WO 9914204 A1; WO 9835937 A1; JP11049743; WO 200018721; WO 200018723; WO 200018724; WO 200017164; WO200017165; WO 200017166; EP 992496; and EP 987251, all of which arehereby incorporated by reference in their entireties for all purposes.

[0071] The invention is useful for CETP inhibitors that havesufficiently low aqueous solubility, low bioavailability or slow rate ofabsorption such that it is desirable to increase their concentration inan aqueous environment of use. Therefore, anytime one finds it desirableto raise the aqueous concentration of the CETP inhibitor in a useenvironment, the invention will find utility. The CETP inhibitor is“substantially water-insoluble” which means that the CETP inhibitor hasa minimum aqueous solubility of less than about 0.01 mg/mL (or 10 μg/ml)at any physiologically relevant pH (e.g., pH 1-8) and at about 22° C.(Unless otherwise specified, reference to aqueous solubility herein andin the claims is determined at about 22° C.) Compositions of the presentinvention find greater utility as the solubility of the CETP inhibitorsdecreases, and thus are preferred for CETP inhibitors with solubilitiesless than about 2 μg/mL, and even more preferred for CETP inhibitorswith solubilities less than about 0.5 μg/mL. Many CETP inhibitors haveeven lower solubilities (some even less than 0.1 μg/mL), and requiredramatic concentration enhancement to be sufficiently bioavailable uponoral dosing for effective plasma concentrations to be reached atpractical doses.

[0072] In general, it may be said that the CETP inhibitor has adose-to-aqueous solubility ratio greater than about 100 mL, where thesolubility (mg/mL) is the minimum value observed in any physiologicallyrelevant aqueous solution (e.g., those with pH values from 1 to 8)including USP simulated gastric and intestinal buffers, and dose is inmg. Compositions of the present invention, as mentioned above, findgreater utility as the solubility of the CETP inhibitor decreases andthe dose increases. Thus, the compositions are preferred as thedose-to-solubility ratio increases, and thus are preferred fordose-to-solubility ratios greater than 1000 mL, and more preferred fordose-to-solubility ratios greater than about 5000 ml. Thedose-to-solubility ratio may be determined by dividing the dose (in mg)by the aqueous solubility (in mg/ml).

[0073] Oral delivery of many CETP inhibitors is particularly difficultbecause their aqueous solubility is usually extremely low, typicallybeing less than 2 μg/ml, often being less than 0.1 μg/ml. Such lowsolubilities are a direct consequence of the particular structuralcharacteristics of species that bind to CETP and thus act as CETPinhibitors. This low solubility is primarily due to the hydrophobicnature of CETP inhibitors. Clog P, defined as the base 10 logarithm ofthe ratio of the drug solubility in octanol to the drug solubility inwater, is a widely accepted measure of hydrophobicity. In general, ClogP values for CETP inhibitors are greater than 4 and are often greaterthan 5 to 7. Thus, the hydrophobic and insoluble nature of CETPinhibitors as a class pose a particular challenge for oral delivery.Achieving therapeutic drug levels in the blood by oral dosing ofpractical quantities of drug generally requires a large enhancement indrug concentrations in the gastrointestinal fluid and a resulting largeenhancement in bioavailability. Such enhancements in drug concentrationin gastrointestsinal fluid typically need to be at least about 10-foldand often at least about 50-fold or even at least about 200-fold toachieve desired blood levels. Surprisingly, the dispersions of thepresent invention have proven to have the required large enhancements indrug concentration and bioavailability.

[0074] In contrast to conventional wisdom, the relative degree ofenhancement in aqueous concentration and bioavailability generallyimproves for CETP inhibitors as solubility decreases and hydrophobocityincreases. In fact, the inventors have recognized a subclass of theseCETP inhibitors that are essentially aqueous insoluble, highlyhydrophobic, and are characterized by a set of physical properties. Thissubclass exhibits dramatic enhancements in aqueous concentration andbioavailability when formulated using the compositions of the presentinvention.

[0075] The first property of this subclass of essentially insoluble,hydrophobic CETP inhibitors is extremely low aqueous solubility. Byextremely low aqueous solubility is meant that the minimum aqueoussolubility at physiologically relevant pH (pH of 1 to 8) is less thanabout 10 μg/ml and preferably less than about 1 μg/ml.

[0076] A second property is a very high does-to-solubility ratio.Extremely low solubility often leads to poor or slow absorption of thedrug from the fluid of the gastrointestinal tract, when the drug isdosed orally in a conventional manner. For extremely low solubilitydrugs, poor absorption generally becomes progressively more difficult asthe dose (mass of drug given orally) increases. Thus, a second propertyof this subclass of essentially insoluble, hydrophobic CETP inhibitorsis a very high dose (in mg) to solubility (in mg/ml) ratio (ml). By“very high dose-to-solubility ratio” is meant that thedose-to-solubility ratio has a value of at least 1000 ml, and preferablyat least 5,000 ml, and more preferably at least 10,000 ml.

[0077] A third property of this subclass of essentially insoluble,hydrophobic CETP inhibitors is that they are extremely hydrophobic. Byextremely hydrophobic is meant that the Clog P value of the drug, has avalue of at least 4.0, preferably a value of at least 5.0, and morepreferably a value of at least 5.5.

[0078] A fourth property of this subclass of essentially insoluble CETPinhibitors is that they have a low melting point. Generally, drugs ofthis subclass will have a melting point of about 150° C. or less, andpreferably about 140° C. or less.

[0079] Primarily, as a consequence of some or all of these fourproperties, CETP inhibitors of this subclass typically have very lowabsolute bioavailabilities. Specifically, the absolute bioavailibilityof drugs in this subclass when dosed orally in their undispersed stateis less than about 10% and more often less than about 5%.

[0080] Turning now to the chemical structures of specific CETPinhibitors, one class of CETP inhibitors that finds utility with thepresent invention consists of oxy substituted4-carboxyamino-2-methyl-1,2,3,4-tetrahydroquinolines having the FormulaI

[0081] and pharmaceutically acceptable salts, enantiomers, orstereoisomers of said compounds;

[0082] wherein R_(I-1), is hydrogen, Y_(I), W_(I)—X_(I), W_(I)—Y_(I);

[0083] wherein WI is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

[0084] X_(I) is —O—Y_(I), —S—Y_(O), —N(H)—Y_(I) or —N—(Y_(I))₂;

[0085] wherein Y_(I) for each occurrence is independently Z_(I) or afully saturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(I);

[0086] wherein Z_(I) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0087] wherein said Z_(I) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxyl, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxyl,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines; R_(I-3) is hydrogen or Q_(I);

[0088] wherein Q_(I) is a fully saturated, partially unsaturated orfully unsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono-, or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(I);

[0089] wherein V_(I) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0090] wherein said V_(I) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carbamoyl, mono-N- or di-N,N-(C₁-C₆) alkylcarbamoyl, carboxyl,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C6)alkyl or (C₂-C₆)alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxyl,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl or (C₂-C₆)alkenyl substituents are also optionallysubstituted with from one to nine fluorines;

[0091] R_(I-4) is Q_(I-1) or V_(I-1)

[0092] wherein Q_(I-1) is a fully saturated, partially unsaturated orfully unsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono-, or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(I-1);

[0093] wherein V_(I-1) is a partially saturated, fully saturated orfully unsaturated three to six membered ring optionally having one totwo heteroatoms selected independently from oxygen, sulfur and nitrogen;

[0094] wherein said VI-1 substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N- ordi-N,N-(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituent isalso optionally substituted with from one to nine fluorines;

[0095] wherein either R_(I-3) must contain V_(I) or R_(I-4) must containV_(I-1); and R_(I-5), R_(I-6) , R_(I-7) and R_(I-8) are eachindependently hydrogen, hydroxy or oxy wherein said oxy is substitutedwith T_(I) or a partially saturated, fully saturated or fullyunsaturated one to twelve membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one or two heteroatoms selected independently from oxygen,sulfur and nitrogen and said carbon is optionally mono-, di- ortri-substituted independently with halo, said carbon is optionallymono-substituted with hydroxy, said carbon is optionallymono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon chain is optionallymono-substituted with T_(I);

[0096] wherein T_(I) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0097] wherein said T_(I) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines.

[0098] Compounds of Formula I and their methods of manufacture aredisclosed in commonly assigned U.S. Pat. No. 6,140,342, U.S. Pat. No.6,362,198, and European Patent publication 987251, all of which areincorporated herein by reference in their entireties for all purposes.

[0099] In a preferred embodiment, the CETP inhibitor is selected fromone of the following compounds of Formula I:

[0100][2R,4S]4-[(3,5-dichloro-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0101][2R,4S]4-[(3,5-dinitro-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0102][2R,4S]4-[(2,6-dichloro-pyridin-4-ylmethyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;

[0103][2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;

[0104][2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0105][2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester,

[0106][2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0107][2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-ethoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0108][2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid 2,2,2-trifluoro-ethylester;

[0109][2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester;

[0110][2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester;

[0111][2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-6-trifluoromethoxy-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester,

[0112][2R,4S](3,5-bis-trifluoromethyl-benzyl)-(1-butyryl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamicacid methyl ester;

[0113][2R,4S](3,5-bis-trifluoromethyl-benzyl)-(1-butyl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamicacid methyl ester; and

[0114][2R,4S](3,5-bis-trifluoromethyl-benzyl)-[1-(2-ethyl-butyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-carbamicacid methyl ester, hydrochloride.

[0115] Another class of CETP inhibitors that finds utility with thepresent invention consists of4-carboxyamino-2-methyl-1,2,3,4,-tetrahydroquinolines, having theFormula II

[0116] and pharmaceutically acceptable salts, enantiomers, orstereoisomers of said compounds;

[0117] wherein R_(II-1) is hydrogen, Y_(II), W_(II)—X_(II),W_(II)—Y_(II);

[0118] wherein W_(II) is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

[0119] X_(II) is —O—Y_(II), —S—Y_(II), —N(H)—Y_(II), or —N—(Y_(II))₂;

[0120] wherein Y_(II), for each occurrence is independently Z_(II), or afully saturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(II);

[0121] Z_(II) is a partially saturated, fully saturated or fullyunsaturated three to twelve membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0122] wherein said Z_(II) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl is also optionally substituted with from one to ninefluorines;

[0123] R_(II-3) is hydrogen or Q_(II);

[0124] wherein Q_(II) is a fully saturated, partially unsaturated orfully unsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(II),;

[0125] wherein V_(II), is a partially saturated, fully saturated orfully unsaturated three to twelve membered ring optionally having one tofour heteroatoms selected independently from oxygen, sulfur andnitrogen, or, a bicyclic ring consisting of two fused partiallysaturated, fully saturated or fully unsaturated three to six memberedrings, taken independently, optionally having one to four heteroatomsselected independently from nitrogen, sulfur and oxygen;

[0126] wherein said VI, substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxamoyl, mono-N- or di-N,N-(C₁-C₆) alkylcarboxamoyl, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino or said(C₁-C₆)alkyl or (C₂-C₆)alkenyl substituents are optionally substitutedwith from one to nine fluorines;

[0127] R_(II-4) is Q_(II-1) or V_(II‘,)

[0128] wherein Q_(II-1) a fully saturated, partially unsaturated orfully unsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(II-1);

[0129] wherein V_(II-1) is a partially saturated, fully saturated orfully unsaturated three to six membered ring optionally having one totwo heteroatoms selected independently from oxygen, sulfur and nitrogen;

[0130] wherein said V_(II-1) substituent is optionally mono-, di-, tri-,or tetra-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N- ordi-N,N-(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituent isoptionally substituted with from one to nine fluorines;

[0131] wherein either R_(II-3) must contain V_(II) or R_(II-4) mustcontain V_(II-1); and

[0132] R_(II-5), R_(II-6), R_(II-7) and R_(II-8) are each independentlyhydrogen, a bond, nitro or halo wherein said bond is substituted withT_(II) or a partially saturated, fully saturated or fully unsaturated(C₁-C₁₂) straight or branched carbon chain wherein carbon may optionallybe replaced with one or two heteroatoms selected independently fromoxygen, sulfur and nitrogen wherein said carbon atoms are optionallymono-, di- or tri-substituted independently with halo, said carbon isoptionally mono-substituted with hydroxy, said carbon is optionallymono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon is optionally mono-substitutedwith T_(II);

[0133] wherein T_(II), is a partially saturated, fully saturated orfully unsaturated three to twelve membered ring optionally having one tofour heteroatoms selected independently from oxygen, sulfur andnitrogen, or, a bicyclic ring consisting of two fused partiallysaturated, fully saturated or fully unsaturated three to six memberedrings, taken independently, optionally having one to four heteroatomsselected independently from nitrogen, sulfur and oxygen;

[0134] wherein said T_(II) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines; provided that at least one of substituents R_(II-5),R_(II-6), R_(II-7) and R_(II-8) is not hydrogen and is not linked to thequinoline moiety through oxy.

[0135] Compounds of Formula II and their methods of manufacture aredisclosed in commonly assigned U.S. Pat. No. 6,147,090, U.S. patentapplication Ser. No. 09/671,400 filed Sep. 27, 2000, and PCT PublicationNo. WO00/17166, all of which are incorporated herein by reference intheir entireties for all purposes.

[0136] In a preferred embodiment, the CETP inhibitor is selected fromone of the following compounds of Formula II:

[0137][2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0138][2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-chloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0139][2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-chloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0140][2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2,6,7-trimethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0141][2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-diethyl-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0142][2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-ethyl-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0143][2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester; and

[0144][2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

[0145] Another class of CETP inhibitors that finds utility with thepresent invention consists of annulated4-carboxyamino-2-methyl-1,2,3,4,-tetrahydroquinolines, having theFormula III

[0146] and pharmaceutically acceptable salts, enantiomers, orstereoisomers of said compounds;

[0147] wherein R_(III-1) is hydrogen, Y_(III), W_(III)—X_(III),W_(III)-Y_(III):

[0148] wherein W_(III) is a carbonyl, thiocarbonyl, sulfinyl orsulfonyl;

[0149] X_(III) is —O—Y_(III), —S—Y_(III), —N(H)—Y_(III) or—N—(Y_(III))₂;

[0150] Y_(III) for each occurrence is independently Z_(III) or a fullysaturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(III);

[0151] wherein Z_(III) is a partially saturated, fully saturated orfully unsaturated three to twelve membered ring optionally having one tofour heteroatoms selected independently from oxygen, sulfur andnitrogen, or a bicyclic ring consisting of two fused partiallysaturated, fully saturated or fully unsaturated three to six memberedrings, taken independently, optionally having one to four heteroatomsselected independently from nitrogen, sulfur and oxygen;

[0152] wherein said Z_(III) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl optionally substituted with from one to nine fluorines;

[0153] R_(III-3) is hydrogen or Q_(III);

[0154] wherein Q_(III) is a fully saturated, partially unsaturated orfully unsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(III);

[0155] wherein V_(III) is a partially saturated, fully saturated orfully unsaturated three to twelve membered ring optionally having one tofour heteroatoms selected independently from oxygen, sulfur andnitrogen, or a bicyclic ring consisting of two fused partiallysaturated, fully saturated or fully unsaturated three to six memberedrings, taken independently, optionally having one to four heteroatomsselected independently from nitrogen, sulfur and oxygen;

[0156] wherein said V_(III) substituent is optionally mono-, di-, tri-,or tetra-substituted independently with halo, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro,cyano, oxo, carboxamoyl, mono-N- or di-N,N-(C₁-C₆) alkylcarboxamoyl,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-₁-C₆)alkylaminowherein said (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionallymono-, di- or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino or said(C₁-C₆)alkyl or (C₂-C₆)alkenyl are optionally substituted with from oneto nine fluorines;

[0157] R_(III-4) is Q_(III-1) or V_(III-1);

[0158] wherein Q_(III) a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(III-1);

[0159] wherein V_(III-1) is a partially saturated, fully saturated orfully unsaturated three to six membered ring optionally having one totwo heteroatoms selected independently from oxygen, sulfur and nitrogen;

[0160] wherein said V_(III-1) substituent is optionally mono-, di-,tri-, or tetra-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N- ordi-N,N-(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituentoptionally having from one to nine fluorines;

[0161] wherein either R_(III-3) must contain V_(III) or R_(III-4) mustcontain V_(III-1); and R_(III-5) and R_(III-6) or R_(III-6) andR_(III-7) and/or R_(III-7) and R_(III-8) are taken together and form atleast one four to eight membered ring that is partially saturated orfully unsaturated optionally having one to three heteroatomsindependently selected from nitrogen, sulfur and oxygen;

[0162] wherein said ring or rings formed by R_(III-5) and R_(III-6), orR_(III-6) and R_(III-7), and/or R_(III-7) and R_(III-8) are optionallymono-, di- or tri-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₄)alkylsulfonyl, (C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent optionally having from one to nine fluorines;

[0163] provided that the R_(III-5), R_(III-6), R_(III-7) and/orR_(III-8), as the case may be, that do not form at least one ring areeach independently hydrogen, halo, (C₁-C₆)alkoxy or (C₁-C₆)alkyl, said(C₁-C₆)alkyl optionally having from one to nine fluorines.

[0164] Compounds of Formula III and their methods of manufacture aredisclosed in commonly assigned U.S. Pat. No. 6,147,089, U.S. Pat. No.6,310,075, and European Patent Application No. 99307240.4 filed Sep. 14,1999, all of which are incorporated herein by reference in theirentireties for all purposes.

[0165] In a preferred embodiment, the CETP inhibitor is selected fromone of the following compounds of Formula III:

[0166] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-2,3,4,6,7,8-hexahydro-cyclopenta[g]quinoline-1-carboxylicacid ethyl ester;

[0167] [6R,8S]8-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-methyl-3,6,7,8-tetrahydro-1H-2-thia-5-aza-cyclopenta[b]naphthalene-5-carboxylicacid ethyl ester;

[0168] [6R,8S]8-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-methyl-3,6,7,8-tetrahydro-2H-furo[2,3-g]quinoline-5-carboxylicacid ethyl ester;

[0169][2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-3,4,6,8-tetrahydro-2H-furo[3,4-g]quinoline-1-carboxylicacid ethyl ester;

[0170][2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-3,4,6,7,8,9-hexahydro-2H-benzo[g]quinoline-1-carboxylicacid propyl ester;

[0171][7R,9S]9-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-5methyl-1,2,3,7,8,9-hexahydro-6-aza-cyclopenta[a]naphthalene-6-carboxylicacid ethyl ester; and

[0172][6S,8R]6-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-8-methyl-1,2,3,6,7,8-hexahydro-9-aza-cyclopenta[a]naphthalene-9-carboxylicacid ethyl ester.

[0173] Another class of CETP inhibitors that finds utility with thepresent invention consists of4-carboxyamino-2-substituted-1,2,3,4,-tetrahydroquinolines, having theFormula IV

[0174] and pharmaceutically acceptable salts, enantiomers, orstereoisomers of said compounds;

[0175] wherein R_(IV-1) is hydrogen, Y_(IV), W_(IV)—X_(IV) orW_(IV)—Y_(IV);

[0176] wherein W_(IV) is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

[0177] X_(IV) is —O—Y_(IV), —S—Y_(IV), —N(H)—Y_(IV) or —N—(Y_(IV))₂;

[0178] wherein Y_(IV) for each occurrence is independently Z_(IV) or afully saturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(IV);

[0179] wherein Z_(IV) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0180] wherein said Z_(IV) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines; R_(IV-2) is a partially saturated, fully saturated orfully unsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one or two heteroatoms selected independently from oxygen,sulfur and nitrogen wherein said carbon atoms are optionally mono-, di-or tri-substituted independently with halo, said carbon is optionallymono-substituted with oxo, said carbon is optionally mono-substitutedwith hydroxy, said sulfur is optionally mono- or di-substituted withoxo, said nitrogen is optionally mono- or di-substituted with oxo; orsaid R_(IV-2) is a partially saturated, fully saturated or fullyunsaturated three to seven membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen,wherein said R_(IV-2) ring is optionally attached through (C₁-C₄)alkyl;

[0181] wherein said R_(IV-2) ring is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, oxo or (C₁-C₆)alkyloxycarbonyl;

[0182] with the proviso that R_(IV-2) is not methyl;

[0183] R_(IV-3) is hydrogen or Q_(IV);

[0184] wherein Q_(IV) is a fully saturated, partially unsaturated orfully unsaturated one to six membered straight or branched carbon chainwherein the carbons other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(IV);

[0185] wherein V_(IV) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0186] wherein said V_(IV) substituent is optionally mono-, di-, tri-,or tetra-substituted independently with halo, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro,cyano, oxo, carboxamoyl, mono-N- or di-N,N-(C₁-C₆) alkylcarboxamoyl,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionallymono-, di- or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(Cl-C₆)alkylamino, said(C₁-C₆)alkyl or (C₂-C₆)alkenyl substituents are also optionallysubstituted with from one to nine fluorines;

[0187] R_(IV-4) is Q_(IV-4) or V_(IV-1);

[0188] wherein Q_(IV-1) a fully saturated, partially unsaturated orfully unsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(IV-1);

[0189] wherein V_(IV), is a partially saturated, fully saturated orfully unsaturated three to six membered ring optionally having one totwo heteroatoms selected independently from oxygen, sulfur and nitrogen;

[0190] wherein said V_(IV-1) substituent is optionally mono-, di-, tri-,or tetra-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N- ordi-N,N-(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituent isalso optionally substituted with from one to nine fluorines;

[0191] wherein either R_(IV-3) must contain V_(IV) or R_(IV-4) mustcontain V_(IV-1); R_(IV-5), R_(IV-6), R_(IV-7) and R_(IV-8) are eachindependently hydrogen, a bond, nitro or halo wherein said bond issubstituted with T_(IV) or a partially saturated, fully saturated orfully unsaturated (C₁-C₁₂) straight or branched carbon chain whereincarbon, may optionally be replaced with one or two heteroatoms selectedindependently from oxygen, sulfur and nitrogen wherein said carbon atomsare optionally mono-, di- or tri-substituted independently with halo,said carbon is optionally mono-substituted with hydroxy, said carbon isoptionally mono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon is optionally mono-substitutedwith T_(IV);

[0192] wherein T_(IV) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0193] wherein said T_(IV) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines; and

[0194] wherein R_(IV-5) and R_(IV-6), or R_(IV-6) and R_(IV-7), and/orR_(IV-7) and R_(IV-8) may also be taken together and can form at leastone four to eight membered ring that is partially saturated or fullyunsaturated optionally having one to three heteroatoms independentlyselected from nitrogen, sulfur and oxygen;

[0195] wherein said ring or rings formed by R_(IV-5) and R_(IV-6), orR_(IV-6) and R_(IV-7), and/or R_(IV-7) and R_(IV-8) are optionallymono-, di- or tri-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₄)alkylsulfonyl, (C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(Cl-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines; with the proviso that when R_(IV-2) is carboxyl or(C₁-C₄)alkylcarboxyl, then R_(IV-1) is not hydrogen.

[0196] Compounds of Formula IV and their methods of manufacture aredisclosed in commonly assigned U.S. Pat. No. 6,197,786, U.S. applicationSer. No. 09/685,3000 filed Oct. 10, 2000 and PCT Publication No. WO00/17164, all of which are incorporated herein by reference in theirentireties for all purposes.

[0197] In a preferred embodiment, the CETP inhibitor is selected fromone of the following compounds of Formula IV:

[0198][2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0199][2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-chloro-2-cyclopropyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0200][2S,4S]2-cyclopropyl-4-[(3,5-dichloro-benzyl)-methoxycarbonyl-amino]-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0201][2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester;

[0202][2R,4R]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinaline-1-carboxylicacid isopropyl ester;

[0203][2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0204][2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclobutyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester;

[0205][2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0206][2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0207][2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid 2-hydroxy-ethyl ester;

[0208][2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0209][2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0210][2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester; and

[0211][2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester.

[0212] Another class of CETP inhibitors that finds utility with thepresent invention consists of 4-aminosubstituted-2-substituted-1,2,3,4,-tetrahydroquinolines, having theFormula V

[0213] and pharmaceutically acceptable salts, enantiomers, orstereoisomers of said compounds;

[0214] wherein R_(V-1) is Y_(V), W_(V)—X_(V) or W_(V)—Y_(V);

[0215] wherein W_(V) is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

[0216] X_(V) is —O—Y_(V), —S—Y_(V), —N(H)—Y_(V) or —N—(Y_(V))₂;

[0217] wherein Y_(V) for each occurrence is independently Z_(V) or afully saturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(V);

[0218] wherein Z_(V) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0219] wherein said Z_(V) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines;

[0220] R_(V-2) is a partially saturated, fully saturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one or two heteroatoms selected independently from oxygen,sulfur and nitrogen wherein said carbon atoms are optionally mono-, di-or tri-substituted independently with halo, said carbon is optionallymono-substituted with oxo, said carbon is optionally mono-substitutedwith hydroxy, said sulfur is optionally mono- or di-substituted withoxo, said nitrogen is optionally mono- or di-substituted with oxo; orsaid R_(V-2) is a partially saturated, fully saturated or fullyunsaturated three to seven membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen,wherein said R_(V-2) ring is optionally attached through (C₁-C₄)alkyl;

[0221] wherein said R_(V-2) ring is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, oxo or (C₁-C₆)alkyloxycarbonyl;

[0222] R_(V-3) is hydrogen or Q_(V);

[0223] wherein Q_(V) is a fully saturated, partially unsaturated orfully unsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono-, or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(V);

[0224] wherein V_(V) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0225] wherein said V_(V) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxamoyl, mono-N- or di-N,N-(C₁-C₆) alkylcarboxamoyl, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl or (C₂-C₆)alkenyl substituents are also optionallysubstituted with from one to nine fluorines;

[0226] R_(V-4) is cyano, formyl, W_(V-1)Q_(V-1), W_(V-1)V_(V-1)(C₁-C₄)alkyleneV_(V-1) or V_(V-2);

[0227] wherein W_(V-1) is carbonyl, thiocarbonyl, SO or SO₂,

[0228] wherein Q_(V-1) a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons may optionally be replaced with one heteroatomselected from oxygen, sulfur and nitrogen and said carbon is optionallymono-, di- or tri-substituted independently with halo, said carbon isoptionally mono-substituted with hydroxy, said carbon is optionallymono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono-, ordi-substituted with oxo, and said carbon chain is optionallymono-substituted with V_(V-1);

[0229] wherein V_(V-1) is a partially saturated, fully saturated orfully unsaturated three to six membered ring optionally having one totwo heteroatoms selected independently from oxygen, sulfur and nitrogen,or a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0230] wherein said V_(V-1) substituent is optionally mono-, di-, tri-,or tetra-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, hydroxy, oxo, amino, nitro, cyano,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-substituted with oxo,said (C₁-C₆)alkyl substituent is also optionally substituted with fromone to nine fluorines;

[0231] wherein V_(V-2) is a partially saturated, fully saturated orfully unsaturated five to seven membered ring containing one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen;

[0232] wherein said V_(V-2) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₂)alkyl, (C₁-C₂)alkoxy,hydroxy, or oxo wherein said (C₁-C₂)alkyl optionally has from one tofive fluorines; and

[0233] wherein R_(V-4) does not include oxycarbonyl linked directly tothe C⁴ nitrogen;

[0234] wherein either R_(V-3) must contain V_(V) or R_(V-4) must containV_(V-1);

[0235] R_(V-5), R_(V-6), R_(V-7) and R_(V-8) are independently hydrogen,a bond, nitro or halo wherein said bond is substituted with T_(V) or apartially saturated, fully saturated or fully unsaturated (C₁-C₁₂)straight or branched carbon chain wherein carbon may optionally bereplaced with one or two heteroatoms selected independently from oxygen,sulfur and nitrogen, wherein said carbon atoms are optionally mono-, di-or tri-substituted independently with halo, said carbon is optionallymono-substituted with hydroxy, said carbon is optionallymono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon chain is optionallymono-substituted with T_(V);

[0236] wherein T_(V) is a partially saturated, fully saturated or fullyunsaturated three to twelve membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0237] wherein said T_(V) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent also optionally has from one to nine fluorines;

[0238] wherein R_(V-5) and R_(V-6), or R_(V-6) and R_(V-7), and/orR_(V-7) and R_(V-8) may also be taken together and can form at least onering that is a partially saturated or fully unsaturated four to eightmembered ring optionally having one to three heteroatoms independentlyselected from nitrogen, sulfur and oxygen;

[0239] wherein said rings formed by R_(V-5) and R_(V-6) or R_(V-6) andR_(V-7), and/or R_(V-7) and R_(V-8) are optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₄)alkylsulfonyl, (C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(Cl-C₆)alkyloxycarbonyl, mono- N- or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent also optionally has from one to nine fluorines.

[0240] Compounds of Formula V and their methods of manufacture aredisclosed in commonly assigned U.S. Pat. No. 6,140,343, U.S. patentapplication Ser. No. 09/671,221 filed Sep. 27, 2000, and PCT PublicationNo. WO 00/17165, all of which are incorporated herein by reference intheir entireties for all purposes.

[0241] In a preferred embodiment, the CETP inhibitor is selected fromone of the following compounds of Formula V:

[0242][2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0243][2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester;

[0244][2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester;

[0245][2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0246][2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0247][2S,4S]4-[1-(3,5-bis-trifluoromethyl-benzyl)-ureido]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0248][2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0249][2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0250][2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester;

[0251][2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0252][2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0253][2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0254][2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0255][2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0256][2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0257][2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester; and

[0258][2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

[0259] Another class of CETP inhibitors that finds utility with thepresent invention consists of cycloalkano-pyridines having the FormulaVI

[0260] and pharmaceutically acceptable salts, enantiomers, orstereoisomers of said compounds;

[0261] in which

[0262] A_(VI) denotes an aryl containing 6 to 10 carbon atoms, which isoptionally substituted with up to five identical or differentsubstituents in the form of a halogen, nitro, hydroxyl, trifluoromethyl,trifluoromethoxy or a straight-chain or branched alkyl, acyl,hydroxyalkyl or alkoxy containing up to 7 carbon atoms each, or in theform of a group according to the formula —BNR_(VI-3)R_(VI-4), wherein

[0263] R_(VI-3) and R_(VI-4) are identical or different and denote ahydrogen, phenyl or a straight-chain or branched alkyl containing up to6 carbon atoms,

[0264] D_(VI) denotes an aryl containing 6 to 10 carbon atoms, which isoptionally substituted with a phenyl, nitro, halogen, trifluoromethyl ortrifluoromethoxy, or a radical according to the formulaR_(VI-5)—L_(VI)—,

[0265] or R_(VI-9)-T_(VI)-V_(VI)-X_(VI), wherein

[0266] R_(VI-5), R_(VI-6) and R_(VI-9) denote, independently from oneanother, a cycloalkyl containing 3 to 6 carbon atoms, or an arylcontaining 6 to 10 carbon atom or a 5- to 7-membered, optionallybenzo-condensed, saturated or unsaturated, mono-, bi- or tricyclicheterocycle containing up to 4 heteroatoms from the series of S, Nand/or O, wherein the rings are optionally substituted, in the case ofthe nitrogen-containing rings also via the N function, with up to fiveidentical or different substituents in the form of a halogen,trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, astraight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxyor alkoxycarbonyl containing up to 6 carbon atoms each, an aryl ortrifluoromethyl-substituted aryl containing 6 to 10 carbon atoms each,or an optionally benzo-condensed, aromatic 5- to 7-membered heterocyclecontaining up to 3 heteoatoms from the series of S, N and/or O, and/orin the form of a group according to the formula BOR_(VI-10),—SR_(VI-11), —SO₂R_(VI-12) or BNR_(VI-13)R_(VI-14), wherein

[0267] R_(VI-10), R_(VI-11) and R_(VI-12) denote, independently from oneanother, an aryl containing 6 to 10 carbon atoms, which is in turnsubstituted with up to two identical or different substituents in theform of a phenyl, halogen or a straight-chain or branched alkylcontaining up to 6 carbon atoms, R_(VI-13) and R_(VI-14) are identicalor different and have the meaning of R_(VI-3) and R_(VI-4) given above,or

[0268] R_(VI-5) and/or R_(VI-6) denote a radical according to theformula

[0269] R_(VI-7) denotes a hydrogen or halogen, and

[0270] R_(VI-8) denotes a hydrogen, halogen, azido, trifluoromethyl,hydroxyl, trifluoromethoxy, a straight-chain or branched alkoxy or alkylcontaining up to 6 carbon atoms each, or a radical according to theformula

—NR_(VI-15)R_(VI-16),

[0271] wherein

[0272] R_(VI-15) and R_(VI-16) are identical or different and have themeaning of R_(VI-3) and R_(VI-4) given above, or

[0273] R_(VI-7) and R_(VI-8) together form a radical according to theformula ═O or ═NR_(VI-17), wherein

[0274] R_(VI-17) denotes a hydrogen or a straight-chain or branchedalkyl, alkoxy or acyl containing up to 6 carbon atoms each,

[0275] L_(VI) denotes a straight-chain or branched alkylene oralkenylene chain containing up to 8 carbon atoms each, which areoptionally substituted with up to two hydroxyl groups,

[0276] T_(VI) and X_(VI) are identical or different and denote astraight-chain or branched alkylene chain containing up to 8 carbonatoms, or

[0277] T_(VI) or X_(VI) denotes a bond,

[0278] V_(VI) denotes an oxygen or sulfur atom or an BNR_(VI-18) group,wherein

[0279] R_(VI-18) denotes a hydrogen or a straight-chain or branchedalkyl containing up to 6 carbon atoms or a phenyl,

[0280] E_(VI) denotes a cycloalkyl containing 3 to 8 carbon atoms, or astraight-chain or branched alkyl containing up to 8 carbon atoms, whichis optionally substituted with a cycloalkyl containing 3 to 8 carbonatoms or a hydroxyl, or a phenyl, which is optionally substituted with ahalogen or trifluoromethyl,

[0281] R_(VI-1) and R_(VI-2) together form a straight-chain or branchedalkylene chain containing up to 7 carbon atoms, which must besubstituted with a carbonyl group and/or a radical according to theformula

[0282] wherein

[0283] a and b are identical or different and denote a number equaling1, 2 or 3,

[0284] R_(VI-19) denotes a hydrogen atom, a cycloalkyl containing 3 to 7carbon atoms, a straight-chain or branched silylalkyl containing up to 8carbon atoms, or a straight-chain or branched alkyl containing up to 8carbon atoms, which is optionally substituted with a hydroxyl, astraight-chain or a branched alkoxy containing up to 6 carbon atoms or aphenyl, which may in turn be substituted with a halogen, nitro,trifluoromethyl, trifluoromethoxy or phenyl or tetrazole-substitutedphenyl, and an alkyl that is optionally substituted with a groupaccording to the formula BOR_(VI-22), wherein

[0285] R_(VI-22) denotes a straight-chain or branched acyl containing upto 4 carbon atoms or benzyl, or

[0286] R_(VI-19) denotes a straight-chain or branched acyl containing upto 20 carbon atoms or benzoyl, which is optionally substituted with ahalogen, trifluoromethyl, nitro or trifluoromethoxy, or a straight-chainor branched fluoroacyl containing up to 8 carbon atoms,

[0287] R_(VI-20) and R_(VI-21) are identical or different and denote ahydrogen, phenyl or a straight-chain or branched alkyl containing up to6 carbon atoms, or R_(VI-20) and R_(VI-21) together form a 3- to6-membered carbocyclic ring, and a the carbocyclic rings formed areoptionally substituted, optionally also geminally, with up to sixidentical or different substituents in the form of trifluoromethyl,hydroxyl, nitrile, halogen, carboxyl, nitro, azido, cyano, cycloalkyl orcycloalkyloxy containing 3 to 7 carbon atoms each, a straight-chain orbranched alkoxycarbonyl, alkoxy or alkylthio containing up to 6 carbonatoms each, or a straight-chain or branched alkyl containing up to 6carbon atoms, which is in turn substituted with up to two identical ordifferent substituents in the form of a hydroxyl, benzyloxy,trifluoromethyl, benzoyl, a straight-chain or branched alkoxy, oxyacylor carboxyl containing up to 4 carbon atoms each and/or a phenyl, whichmay in turn be substituted with a halogen, trifluoromethyl ortrifluoromethoxy, and/or the carbocyclic rings formed are optionallysubstituted, also geminally, with up to five identical or differentsubstituents in the form of a phenyl, benzoyl, thiophenyl orsulfonylbenzyl, which in turn are optionally substituted with a halogen,trifluoromethyl, trifluoromethoxy or nitro, and/or optionally in theform of a radical according to the formula

[0288] wherein

[0289] c is a number equaling 1, 2, 3 or 4,

[0290] d is a number equaling 0 or 1,

[0291] R_(VI-23) and R_(VI-24) are identical or different and denote ahydrogen, cycloalkyl containing 3 to 6 carbon atoms, a straight-chain orbranched alkyl containing up to 6 carbon atoms, benzyl or phenyl, whichis optionally substituted with up to two identical or differentsubstituents in the form of halogen, trifluoromethyl, cyano, phenyl ornitro, and/or the carbocyclic rings formed are optionally substitutedwith a spiro-linked radical according to the formula

[0292] wherein

[0293] W_(VI) denotes either an oxygen atom or a sulfur atom,

[0294] Y_(VI) and Y=_(VI) together form a 2- to 6-memberedstraight-chain or branched alkylene chain,

[0295] e is a number equaling 1, 2, 3, 4, 5, 6 or 7,

[0296] f is a number equaling 1 or 2,

[0297] R_(VI-25), R_(VI-26),R_(VI-27), R_(VI-28), R_(VI-29), R_(VI-30),and R_(VI-31) are identical or different and denote a hydrogen,trifluoromethyl, phenyl, halogen or a straight-chain or branched alkylor alkoxy containing up to 6 carbon atoms each, or

[0298] R_(VI-25) and R_(VI-26) or R_(VI-27) and R_(VI-28) each togetherdenote a straight-chain or branched alkyl chain containing up to 6carbon atoms or

[0299] R_(VI-25) and R_(VI-26) or R_(VI-27) and R_(VI-28) each togetherform a radical according to the formula

[0300] wherein

[0301] W_(VI) has the meaning given above,

[0302] g is a number equaling 1, 2, 3, 4, 5, 6 or 7,

[0303] R_(VI-32) and R_(VI-33) together form a 3- to 7-memberedheterocycle, which contains an oxygen or sulfur atom or a groupaccording to the formula SO, SO₂ or BNR_(VI-34), wherein

[0304] R_(VI-34) denotes a hydrogen atom, a phenyl, benzyl, or astraight-chain or branched alkyl containing up to 4 carbon atoms, andsalts and N oxides thereof, with the exception of 5(6H)-quinolones,3-benzoyl-7,8-dihydro-2,7,7-trimethyl-4-phenyl.

[0305] Compounds of Formula VI and their methods of manufacture aredisclosed in European Patent Application No. EP 818448 A1, U.S. Pat. No.6,207,671 and U.S. Pat. No. 6,069,148, all of which are incorporatedherein by reference in their entireties for all purposes.

[0306] In a preferred embodiment, the CETP inhibitor is selected fromone of the following compounds of Formula VI:

[0307]2-cyclopentyl-4-(4-fluorophenyl)-7,7-dimethyl-3-(4-trifluoromethylbenzoyl)-4,6,7,8-tetrahydro-1H-quinolin-5-one;

[0308]2-cyclopentyl-4-(4-fluorophenyl)-7,7-dimethyl-3-(4-trifluoromethylbenzoyl)-7,8-dihydro-6H-quinolin-5-one;

[0309][2-cyclopentyl-4-(4-fluorophenyl)-5-hydroxy-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-trifluoromethylphenyl)-methanone;

[0310][5-(t-butyldimethylsilanyloxy)-2-cyclopentyl-4-(4-fluorophenyl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-trifluoromethylphenyl)-methanone;

[0311][5-(t-butyidimethylsilanyloxy)-2-cyclopentyl-4-(4-fluorophenyl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-trifluoromethylphenyl)-methanol;

[0312]5-(t-butyldimethylsilanyloxy)-2-cyclopentyl-4-(4-fluorophenyl)-3-[fluoro-(4-trifluoromethylphenyl)-methyl]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline;and

[0313]2-cyclopentyl-4-(4-fluorophenyl)-3-[fluoro-(4-trifluoromethylphenyl)-methyl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol.

[0314] Another class of CETP inhibitors that finds utility with thepresent invention consists of substituted-pyridines having the FormulaVII

[0315] or a pharmaceutically acceptable salt or tautomer thereof,

[0316] wherein

[0317] R_(VII-2) and R_(VII-6) are independently selected from the groupconsisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, fluorinatedaralkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl; provided that atleast one of R_(VII-2) and R_(VII-6) is fluorinated alkyl,chlorofluorinated alkyl or alkoxyalkyl;

[0318] R_(VII-3) is selected from the group consisting of hydroxy,amido, arylcarbonyl, heteroarylcarbonyl, hydroxymethyl

[0319] —CHO,

[0320] —CO₂R_(VII-7), wherein R_(VII-7) is selected from the groupconsisting of hydrogen, alkyl and cyanoalkyl; and

[0321] wherein R_(VII-15a) is selected from the group consisting ofhydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio,arylthio, heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy,aryloxy, heteroaryloxy and heterocyclyloxy, and

[0322] R_(VII-16a) is selected from the group consisting of alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl,and heterocyclyl, arylalkoxy, trialkylsilyloxy;

[0323] R_(VII-4) is selected from the group consisting of hydrogen,hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl,cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl,heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl,hetereoarylalkenyl, heterocyclylalkenyl, alkoxy, alkenoxy, alkynoxy,aryloxy, heteroaryloxy, heterocyclyloxy, alkanoyloxy, alkenoyloxy,alkynoyloxy, aryloyloxy, heteroaroyloxy, heterocyclyloyloxy,alkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, aryloxycarbonyl,heteroaryloxycarbonyl, heterocyclyloxycarbonyl, thio, alkylthio,alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio,cycloalkylthio, cycloalkenylthio, alkylthioalkyl, alkenylthioalkyl,alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl,heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl,alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl,heterocyclythioalkenyl, alkylamino, alkenylamino, alkynylamino,arylamino, heteroarylamino, heterocyclylamino, aryidialkylamino,diarylamino, diheteroarylamino, alkylarylamino, alkylheteroarylamino,arylheteroarylamino, trialkylsilyl, trialkenylsilyl, triarylsilyl,—CO(O)N(R_(VII-8a)R_(VII-8b)), wherein R_(VII-8a) and R_(VII-8b) areindependently selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl and heterocyclyl, —SO₂R_(VII-9), whereinR_(VII-9) is selected from the group consisting of hydroxy, alkyl,alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl,—OP(O)(OR_(VII-10a)) (OR_(VII-10b)), wherein R_(VII-11a) andRV_(VII-11b) are independently selected from the group consisting ofhydrogen, hydroxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl andheterocyclyl, and —OP(S) (OR_(VII-11a)) (OR_(VII-11b)), whereinR_(VII-11a)and R_(VII-11b) are independently selected from the groupconsisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl andheterocyclyl;

[0324] R_(VII-5) is selected from the group consisting of hydrogen,hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl,alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy,alkylcarbonyloxyalkyl, alkenylcarbonyloxyalkyl, alkynylcarbonyloxyalkyl,arylcarbonyloxyalkyl, heteroarylcarbonyloxyalkyl,heterocyclylcarbonyloxyalkyl, cycloalkylalkyl, cycloalkenylalkyl,aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl,cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl,alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl,arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl,alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl,arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl,alkoxyalkyl, alkenoxyalkyl, alkynoxylalkyl, aryloxyalkyl,heteroaryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkenyl,alkenoxyalkenyl, alkynoxyalkenyl, aryloxyalkenyl, heteroaryloxyalkenyl,heterocyclyloxyalkenyl, cyano, hydroxymethyl, —CO₂R_(VII-14), whereinR_(VII-14) is selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl and heterocyclyl;

[0325] wherein R_(VII-15b) is selected from the group consisting ofhydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio,arylthio, heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy,aryloxy, heteroaryloxy, heterocyclyloxy, aroyloxy, and alkylsulfonyloxy,and

[0326] R_(VII-16b) is selected form the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkoxy, andtrialkylsilyloxy;

[0327] wherein R_(VII-17) and R_(VII-18) are independently selected fromthe group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl and heterocyclyl;

[0328] wherein R_(VII-19) is selected from the group consisting ofalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,—SR_(VII-20), —OR_(VII-21), and BR_(VII-22)CO₂R_(VII-23), wherein

[0329] R_(VII-20) is selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aminoalkyl,aminoalkenyl, aminoalkynyl, aminoaryl, aminoheteroaryl,aminoheterocyclyl, alkylheteroarylamino, arylheteroarylamino,

[0330] R_(VII-21) is selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl,

[0331] R_(VII-22) is selected from the group consisting of alkylene orarylene, and

[0332] R_(VII-23) is selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;

[0333] wherein R_(VII-24) is selected from the group consisting ofhydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, aralkyl, aralkenyl, and aralkynyl;

[0334] wherein R_(VII-25) is heterocyclylidenyl;

[0335] wherein R_(VII-26) and R_(VII-27) are independently selected fromthe group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, and heterocyclyl;

[0336] wherein R_(VII-28) and R_(VII-29) are independently selected fromthe group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, and heterocyclyl;

[0337] wherein R_(VII-30) and R_(VII-31) are independently alkoxy,alkenoxy, alkynoxy, aryloxy, heteroaryloxy, and heterocyclyloxy; and

[0338] wherein R_(VII-32) and R_(VII-33) are independently selected fromthe group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, and heterocyclyl;

[0339] wherein R_(VII-36) is selected from the group consisting ofalkyl, alkenyl, aryl, heteroaryl and heterocyclyl;

[0340] wherein R_(VII-37) and R_(VII-38) are independently selected fromthe group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, and heterocyclyl;

[0341] wherein R_(VII-39) is selected from the group consisting ofhydrogen, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy,heterocyclyloxy, alkylthio, alkenylthio, alkynylthio, arylthio,heteroarylthio and heterocyclylthio, and

[0342] R_(VII-40) is selected from the group consisting of haloalkyl,haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl,cycloalkyl, cycloalkenyl, heterocyclylalkoxy, heterocyclylalkenoxy,heterocyclylalkynoxy, alkylthio, alkenylthio, alkynylthio, arylthio,heteroarylthio and heterocyclylthio;

—N═R_(VII-41),

[0343] wherein R_(VII-41) is heterocyclylidenyl;

[0344] wherein R_(VII-42) is selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl,and

[0345] R_(VII-43) is selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl,haloheteroaryl, and haloheterocyclyl;

[0346] wherein R_(VII-44) is selected from the group consisting ofhydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl andheterocyclyl;

—N═S═O;

—N═C═S;

—N═C═O;

—N₃;

—SR_(VII-45)

[0347] wherein R_(VII-45) is selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl,haloheterocyclyl, heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl,aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl,cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl,alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl,arylthioalkyl,heteroarylthioalkyl, heterocyclylthioalkyl,alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl,arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl,aminocarbonylalkyl, aminocarbonylalkenyl, aminocarbonylalkynyl,aminocarbonylaryl, aminocarbonylheteroaryl, andaminocarbonylheterocyclyl,

—SR_(VII-46), and —CH₂R_(VII-47),

[0348] wherein R_(VII-46) is selected from the group consisting ofalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and

[0349] R_(VII-47) is selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl; and

[0350] wherein R_(VII-48) is selected from the group consisting ofhydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl andheterocyclyl, and

[0351] R_(VII-49) is selected from the group consisting of alkoxy,alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, haloalkyl,haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclyl;

[0352] wherein R_(VII-50) is selected from the group consisting ofhydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy andheterocyclyloxy;

[0353] wherein R_(VII-51) is selected from the group consisting ofalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl,haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclyl;and

[0354] wherein R_(VII-53) is selected from the group consisting ofalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;

[0355] provided that when R_(VII-5) is selected from the groupconsisting of heterocyclylalkyl and heterocyclylalkenyl, theheterocyclyl radical of the corresponding heterocyclylalkyl orheterocyclylalkenyl is other than δ-lactone; and

[0356] provided that when R_(VII-4) is aryl, heteroaryl or heterocyclyl,and one of R_(VII-2) and R_(VII-6) is trifluoromethyl, then the other ofR_(VII-2) and R_(VII-6) is difluoromethyl.

[0357] Compounds of Formula VII and their methods of manufacture aredisclosed in PCT Publication No. WO 9941237-A1, which is incorporatedherein by reference in its entirety for all purposes.

[0358] In a preferred embodiment, the CETP inhibitor of Formula VII isdimethyl5,5-dithiobis[2-difluoromethyl-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridine-carboxylate].

[0359] Another class of CETP inhibitors that finds utility with thepresent invention consists of substituted biphenyls having the FormulaVIII

[0360] or a pharmaceutically acceptable salt, enantiomers, orstereoisomers thereof, in which

[0361] A_(VIII) stands for aryl with 6 to 10 carbon atoms, which isoptionally substituted up to 3 times in an identical manner ordifferently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, orby straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbonatoms each, or by a group of the formula

—NR_(VIII-1)R_(VIII-2),

[0362] wherein

[0363] R_(VIII-1) and R_(VIII-2) are identical or different and denotehydrogen, phenyl, or straight-chain or branched alkyl with up to 6carbon atoms,

[0364] D_(VIII) stands for straight-chain or branched alkyl with up to 8carbon atoms, which is substituted by hydroxy,

[0365] E_(VIII) andL_(VIII are either identical or different and stand for straight-chain or branched alkyl with up to)8 carbon atoms, which is optionally substituted by cycloalkyl with 3 to8 carbon atoms, or stands for cycloalkyl with 3 to 8 carbon atoms, or

[0366] E_(VIII) has the above-mentioned meaning and

[0367] L_(VIII) in this case stands for aryl with 6 to 10 carbon atoms,which is optionally substituted up to 3 times in an identical manner ordifferently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, orby straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbonatoms each, or by a group of the formula

—NR_(VIII-3)R_(VIII-4),

[0368] wherein

[0369] R_(VIII-3) and R_(VIII-4) are identical or different and have themeaning given above for R_(VIII-1) and R_(VIII-2), or

[0370] E_(VIII) stands for straight-chain or branched alkyl with up to 8carbon atoms, or stands for aryl with 6 to 10 carbon atoms, which isoptionally substituted up to 3 times in an identical manner ordifferently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, orby straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbonatoms each, or by a group of the formula

—NR_(VIII-5)R_(VIII-6),

[0371] wherein

[0372] R_(VIII-5) and R_(VIII-6) are identical or different and have themeaning given above for R_(VIII-1) and R_(VIII-2), and

[0373] L_(VIII) in this case stands for straight-chain or branchedalkoxy with up to 8 carbon atoms or for cycloalkyloxy with 3 to 8 carbonatoms,

[0374] T_(VIII) stands for a radical of the formula

R_(VIII-7)—X_(VIII-)

[0375] or

[0376] wherein

[0377] R_(VIII-7) and R_(VIII-8) are identical or different and denotecycloalkyl with 3 to 8 carbon atoms, or aryl with 6 to 10 carbon atoms,or denote a 5- to 7-member aromatic, optionally benzo-condensed,heterocyclic compound with up to 3 heteroatoms from the series S, Nand/or O, which are optionally substituted up to 3 times in an identicalmanner or differently by trifluoromethyl, trifluoromethoxy, halogen,hydroxy, carboxyl, by straight-chain or branched alkyl, acyl, alkoxy, oralkoxycarbonyl with up to 6 carbon atoms each, or by phenyl, phenoxy, orthiophenyl, which can in turn be substituted by halogen,trifluoromethyl, or trifluoromethoxy, and/or the rings are substitutedby a group of the formula

—NR_(VIII-11)R_(VIII-12),

[0378] wherein

[0379] R_(VIII-11) and R_(VIII-12) are identical or different and havethe meaning given above for R_(VIII-1) and R_(VIII-2),

[0380] X_(VIII) denotes a straight or branched alkyl chain or alkenylchain with 2 to 10 carbon atoms each, which are optionally substitutedup to 2 times by hydroxy,

[0381] R_(VIII-9) denotes hydrogen, and

[0382] R_(VIII-10) denotes hydrogen, halogen, azido, trifluoromethyl,hydroxy, mercapto, trifluoromethoxy, straight-chain or branched alkoxywith up to 5 carbon atoms, or a radical of the formula

—NR_(VIII-13)R_(VIII-14),

[0383] wherein

[0384] R_(VIII-13) and R_(VIII-14) are identical or different and havethe meaning given above for R_(VIII-1) and R_(VIII-2), or

[0385] R_(VIII-9) and R_(VIII-10) form a carbonyl group together withthe carbon atom.

[0386] Compounds of Formula VIII are disclosed in PCT Publication No. WO9804528, which is incorporated herein by reference in its entirety forall purposes.

[0387] Another class of CETP inhibitors that finds utility with thepresent invention consists of substituted 1,2,4-triazoles having theFormula IX

[0388] or a pharmaceutically acceptable salt or tautomer thereof;

[0389] wherein R_(IX-1) is selected from higher alkyl, higher alkenyl,higher alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl,alkylthioalkyl, arylthioalkyl, and cycloalkylalkyl;

[0390] wherein R_(IX-2) is selected from aryl, heteroaryl, cycloalkyl,and cycloalkenyl, wherein R_(IX-2) is optionally substituted at asubstitutable position with one or more radicals independently selectedfrom alkyl, haloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxy,halo, aryloxy, aralkyloxy, aryl, aralkyl, aminosulfonyl, amino,monoalkylamino and dialkylamino; and

[0391] wherein R_(IX-3) is selected from hydrido, —SH and halo; providedR_(IX-2) cannot be phenyl or 4-methylphenyl when R_(IX-1) is higheralkyl and when R_(IX-3) is BSH.

[0392] Compounds of Formula IX and their methods of manufacture aredisclosed in PCT Publication No. WO 9914204, which is incorporatedherein by reference in its entirety for all purposes.

[0393] In a preferred embodiment, the CETP inhibitor is selected fromthe following compounds of Formula IX:

[0394]2,4-dihydro-4-(3-methoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0395]2,4-dihydro-4-(2-fluorophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0396]2,4-dihydro-4-(2-methylphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0397]2,4-dihydro-4-(3-chlorophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0398]2,4-dihydro-4-(2-methoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0399]2,4-dihydro-4-(3-methylphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0400] 4-cyclohexyl-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0401] 2,4-dihydro-4-(3-pyridyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0402]2,4-dihydro-4-(2-ethoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0403]2,4-dihydro-4-(2,6-dimethylphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0404]2,4-dihydro-4-(4-phenoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0405]4-(1,3-benzodioxol-5-yl)-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0406]4-(2-chlorophenyl)-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0407]2,4-dihydro-4-(4-methoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0408]2,4-dihydro-5-tridecyl-4-(3-trifluoromethylphenyl)-3H-1,2,4-triazole-3-thione;

[0409]2,4-dihydro-5-tridecyl-4-(3-fluorophenyl)-3H-1,2,4-triazole-3-thione;

[0410]4-(3-chloro-4-methylphenyl)-2.4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0411]2,4-dihydro-4-(2-methylthiophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0412]4-(4-benzyloxyphenyl)-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0413] 2,4-dihydro-4-(2-naphthyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0414]2,4-dihydro-5-tridecyl-4-(4-trifluoromethylphenyl)-3H-1,2,4-triazole-3-thione;

[0415] 2,4-dihydro-4-(1-naphthyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0416]2,4-dihydro-4-(3-methylthiophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0417]2,4-dihydro-4-(4-methylthiophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0418]2,4-dihydro-4-(3,4-dimethoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0419]2,4-dihydro-4-(2,5-dimethoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0420]2,4-dihydro-4-(2-methoxy-5-chlorophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0421]4-(4-aminosulfonylphenyl)-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0422]2,4-dihydro-5-dodecyl-4-(3-methoxyphenyl)-3H-1,2,4-triazole-3-thione;

[0423]2,4-dihydro-4-(3-methoxyphenyl)-5-tetradecyl-3H-1,2,4-triazole-3-thione;

[0424]2,4-dihydro-4-(3-methoxyphenyl)-5-undecyl-3H-1,2,4-triazole-3-thione;and

[0425]2,4-dihydro-(4-methoxyphenyl)-5-pentadecyl-3H-1,2,4-triazole-3-thione.

[0426] Another class of CETP inhibitors that finds utility with thepresent invention consists of hetero-tetrahydroquinolines having theFormula X

[0427] and pharmaceutically acceptable salts, enantiomers, orstereoisomers or N-oxides of said compounds;

[0428] in which

[0429] A_(X) represents cycloalkyl with 3 to 8 carbon atoms or a 5 to7-membered, saturated, partially saturated or unsaturated, optionallybenzo-condensed heterocyclic ring containing up to 3 heteroatoms fromthe series comprising S, N and/or O, that in case of a saturatedheterocyclic ring is bonded to a nitrogen function, optionally bridgedover it, and in which the aromatic systems mentioned above areoptionally substituted up to 5-times in an identical or differentsubstituents in the form of halogen, nitro, hydroxy, trifluoromethyl,trifluoromethoxy or by a straight-chain or branched alkyl, acyl,hydroxyalkyl or alkoxy each having up to 7 carbon atoms or by a group ofthe formula BNR_(X-3)R_(X-4),

[0430] in which

[0431] R_(X-3) and R_(X-4) are identical or different and denotehydrogen, phenyl or straight-chain or branched alkyl having up to 6carbon atoms,

[0432] or

[0433] A_(X) represents a radical of the formula

[0434] D_(X) represents an aryl having 6 to 10 carbon atoms, that isoptionally substituted by phenyl, nitro, halogen, trifluormethyl ortrifluormethoxy, or it represents a radical of the formula

[0435] in which

[0436] R_(X-5), R_(X-6) and R_(X-9) independently of one another denotecycloalkyl having 3 to 6 carbon atoms, or an aryl having 6 to 10 carbonatoms or a 5- to 7-membered aromatic, optionally benzo-condensedsaturated or unsaturated, mono-, bi-, or tricyclic heterocyclic ringfrom the series consisting of S, N and/or O, in which the rings aresubstituted, optionally, in case of the nitrogen containing aromaticrings via the N function, with up to 5 identical or differentsubstituents in the form of halogen, trifluoromethyl, nitro, hydroxy,cyano, carbonyl, trifluoromethoxy, straight straight-chain or branchedacyl, alkyl, alkylthio, alkylalkoxy, alkoxy, or alkoxycarbonyl eachhaving up to 6 carbon atoms, by aryl or trifluoromethyl-substituted aryleach having 6 to 10 carbon atoms or by an, optionally benzo-condensed,aromatic 5- to 7-membered heterocyclic ring having up to 3 heteroatomsfrom the series consisting of S, N, and/or O, and/or substituted by agroup of the formula BOR_(X-10), —SR_(X-11), SO₂R_(X-12) orBNR_(X-13)R_(X-14),

[0437] in which

[0438] R_(X-10), R_(X-11) and R_(X-12) independently from each otherdenote aryl having 6 to 10 carbon atoms, which is in turn substitutedwith up to 2 identical or different substituents in the form of phenyl,halogen or a straight-chain or branched alkyl having up to 6 carbonatoms,

[0439] R_(X-13) and R_(X-14) are identical or different and have themeaning of R_(X-3) and R_(X-4) indicated above,

[0440] or

[0441] R_(X-5) and/or R_(X-6) denote a radical of the formula

[0442] R_(X-7) denotes hydrogen or halogen, and

[0443] R_(X-8) denotes hydrogen, halogen, azido, trifluoromethyl,hydroxy, trifluoromethoxy, straight-chain or branched alkoxy or alkylhaving up to 6 carbon atoms or a radical of the formula

BNR_(X-15)R_(X-16),

[0444] in which

[0445] R_(X-15) and R_(X-16) are identical or different and have themeaning of R_(X-3) and R_(X-4) indicated above,

[0446] or

[0447] R_(X-7) and R_(X-8) together form a radical of the formula ═O or═NR_(X-17),

[0448] in which

[0449] R_(X-17) denotes hydrogen or straight chain or branched alkyl,alkoxy or acyl having up to 6 carbon atoms,

[0450] L_(X) denotes a straight chain or branched alkylene or alkenylenechain having up to 8 carbon atoms, that are optionally substituted withup to 2 hydroxy groups,

[0451] T_(X) and X_(X) are identical or different and denote a straightchain or branched alkylene chain with up to 8 carbon atoms

[0452] or

[0453] T_(X) or X_(X) denotes a bond,

[0454] V_(X) represents an oxygen or sulfur atom or an BNR_(X-18)-group,in which

[0455] R_(X-18) denotes hydrogen or straight chain or branched alkylwith up to 6 carbon atoms or phenyl,

[0456] E_(X) represents cycloalkyl with 3 to 8 carbon atoms, or straightchain or branched alkyl with up to 8 carbon atoms, that is optionallysubstituted by cycloalkyl with 3 to 8 carbon atoms or hydroxy, orrepresents a phenyl, that is optionally substituted by halogen ortrifluoromethyl,

[0457] R_(X-1) and R_(X-2) together form a straight-chain or branchedalkylene chain with up to 7 carbon atoms, that must be substituted bycarbonyl group and/or by a radical with the formula

[0458] in which a and b are identical or different and denote a numberequaling 1,2, or 3,

[0459] R_(X-19) denotes hydrogen, cycloalkyl with 3 up to 7 carbonatoms, straight chain or branched silylalkyl with up to 8 carbon atomsor straight chain or branched alkyl with up to 8 carbon atoms, that areoptionally substituted by hydroxyl, straight chain or branched alkoxywith up to 6 carbon atoms or by phenyl, which in turn might besubstituted by halogen, nitro, trifluormethyl, trifluoromethoxy or byphenyl or by tetrazole-substituted phenyl, and alkyl, optionally besubstituted by a group with the formula BOR_(X-22),

[0460] in which

[0461] R_(X-22) denotes a straight chain or branched acyl with up to 4carbon atoms or benzyl,

[0462] or

[0463] R_(X-19) denotes straight chain or branched acyl with up to 20carbon atoms or benzoyl, that is optionally substituted by halogen ,trifluoromethyl, nitro or trifluoromethoxy, or it denotes straight chainor branched fluoroacyl with up to 8 carbon atoms and 9 fluorine atoms,

[0464] R_(X-20) and R_(X-21) are identical or different and denotehydrogen, phenyl or straight chain or branched alkyl with up to 6 carbonatoms,

[0465] or

[0466] R_(X-20) and R_(X-21) together form a 3- to 6-memberedcarbocyclic ring, and the carbocyclic rings formed are optionallysubstituted, optionally also geminally, with up to six identical ordifferent substituents in the form of triflouromethyl, hydroxy, nitrile,halogen, carboxyl, nitro, azido, cyano, cycloalkyl or cycloalkyloxy with3 to 7 carbon atoms each, by straight chain or branched alkoxycarbonyl,alkoxy or alkylthio with up to 6 carbon atoms each or by straight chainor branched alkyl with up to 6 carbon atoms, which in turn issubstituted with up to 2 identically or differently by hydroxyl,benzyloxy, trifluoromethyl, benzoyl, straight chain or branched alkoxy,oxyacyl or carbonyl with up to 4 carbon atoms each and/or phenyl, whichmay in turn be substituted with a halogen, trifuoromethyl ortrifluoromethoxy, and/or the formed carbocyclic rings are optionallysubstituted, also geminally, with up to 5 identical or differentsubstituents in the form of phenyl, benzoyl, thiophenyl orsulfonylbenzyl, which in turn are optionally substituted by halogen,trifluoromethyl, trifluoromethoxy or nitro, and/or optionally aresubstituted by a radical with the formula

[0467] in which

[0468] c denotes a number equaling 1, 2, 3, or 4,

[0469] d denotes a number equaling 0 or 1,

[0470] R_(X-23) and R_(X-24) are identical or different and denotehydrogen, cycloalkyl with 3 to 6 carbon atoms, straight chain orbranched alkyl with up to 6 carbon atoms, benzyl or phenyl, that isoptionally substituted with up to 2 identically or differently byhalogen, trifluoromethyl, cyano, phenyl or nitro, and/or the formedcarbocyclic rings are substituted optionally by a spiro-linked radicalwith the formula

[0471] in which

[0472] W_(X) denotes either an oxygen or a sulfur atom

[0473] Y_(X) and Y′_(X) together form a 2 to 6 membered straight chainor branched alkylene chain,

[0474] e denotes a number equaling 1, 2, 3, 4, 5, 6, or 7,

[0475] f denotes a number equaling 1 or 2,

[0476] R_(X-25), R_(X-26), R_(X-27) , R_(X-28), R_(X-29), R_(X-30) andR_(X-31) are identical or different and denote hydrogen,trifluoromethyl, phenyl, halogen or straight chain or branched alkyl oralkoxy with up to 6 carbon atoms each,

[0477] or

[0478] R_(X-25) and R_(X-26) or R_(X-27) and R_(X-28) respectively formtogether a straight chain or branched alkyl chain with up to 6 carbonatoms,

[0479] or

[0480] R_(X-25) and R_(X-26) or R_(X-27) and R_(X-28) each together forma radical with the formula

[0481] in which

[0482] W_(X) has the meaning given above,

[0483] g denotes a number equaling 1, 2, 3, 4, 5, 6, or 7,

[0484] R_(X-32) and R_(X-33) form together a 3- to 7-memberedheterocycle, which contains an oxygen or sulfur atom or a group with theformula SO, SO₂ or —NR_(X-34),

[0485] in which

[0486] R_(X-34) denotes hydrogen, phenyl, benzyl or straight or branchedalkyl with up to 4 carbon atoms.

[0487] Compounds of Formula X and their methods of manufacture aredisclosed in PCT Publication No. WO 9914215, which is incorporatedherein by reference in its entirety for all purposes.

[0488] In a preferred embodiment, the CETP inhibitor is selected fromthe following compounds of Formula X:

[0489]2-cyclopentyl-5-hydroxy-7,7-dimethyl-4-(3-thienyl)-3-(4-trifluoromethylbenxoyl)-5,6,7,8-tetrahydroquinoline;

[0490]2-cyclopentyl-3-[fluoro-(4-trifluoromethylphenyl)methyl]-5-hydroxy-7,7-dimethyl-4-(3-thienyl)-5,6,7,8-tetrahydroquinoline;and

[0491]2-cyclopentyl-5-hydroxy-7,7-dimethyl-4-(3-thienyl)-3-(trifluoromethylbenxyl)-5,6,7,8-tetrahydroquinoline.

[0492] Another class of CETP inhibitors that finds utility with thepresent invention consists of substituted tetrahydro naphthalines andanalogous compound having the Formula XI

[0493] and stereoisomers, stereoisomer mixtures, and salts thereof, inwhich

[0494] A_(XI) stands for cycloalkyl with 3 to 8 carbon atoms, or standsfor aryl with 6 to 10 carbon atoms, or stands for a 5- to 7-membered,saturated, partially unsaturated or unsaturated, possiblybenzocondensated, heterocycle with up to 4 heteroatoms from the seriesS, N and/or O, where aryl and the heterocyclic ring systems mentionedabove are substituted up to 5-fold, identical or different, by cyano,halogen, nitro, carboxyl, hydroxy, trifluoromethyl, trifluoro-methoxy,or by straight-chain or branched alkyl, acyl, hydroxyalkyl, alkylthio,alkoxycarbonyl, oxyalkoxycarbonyl or alkoxy each with up to 7 carbonatoms, or by a group of the formula

—NR_(XI-3)R_(XI-4),

[0495] in which

[0496] R_(XI-3) and R_(XI-4) are identical or different and denotehydrogen, phenyl, or straight-chain or branched alkyl with up to 6carbon atoms

[0497] D_(XI) stands for a radical of the formula

[0498] in which

[0499] R_(XI-5), R_(XI-6) and R_(XI-9), independent of each other,denote cycloalkyl with 3 to 6 carbon atoms, or denote aryl with 6 to 10carbon atoms, or denote a 5- to 7-membered, possibly benzocondensated,saturated or unsaturated, mono-, bi- or tricyclic heterocycle with up to4 heteroatoms of the series S, N and/or O, where the cycles are possiblysubstitutedCin the case of the nitrogen-containing rings also via theN-functionCup to 5-fold, identical or different, by halogen,trifluoromethyl. nitro, hydroxy, cyano, carboxyl, trifluoromethoxy,straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxyor alkoxycarbonyl with up to 6 carbon atoms each. by aryl ortrifluoromethyl substituted aryl with 6 to 10 carbon atoms each, or by apossibly benzocondensated aromatic 5- to 7-membered heterocycle with upto 3 heteroatoms of the series S, N and/or O, and/or are substituted bya group of the formula

—OR_(XI-10), —SR_(XI-11), —SO₂R_(XI-12) or —NR_(XI-13)R_(XI-14),

[0500] in which

[0501] R_(XI-10), R_(XI-11) and R_(XI-12), independent of each other,denote aryl with 6 to 10 carbon atoms, which itself is substituted up to2-fold, identical or different, by phenyl, halogen. or by straight-chainor branched alkyl with up to 6 carbon atoms,

[0502] R_(XI-13) and R_(XI-14) are identical or different and have themeaning given above for R_(XI-3) and R_(XI-4),

[0503] or

[0504] R_(XI-5) and/or R_(XI-6) denote a radical of the formula

[0505] R_(XI-7) denotes hydrogen, halogen or methyl,

[0506] and

[0507] R_(XI-8) denotes hydrogen, halogen, azido, trifluoromethyl,hydroxy, trifluoromethoxy, straight-chain or branched alkoxy or alkylwith up to 6 carbon atoms each, or a radical of the formula—NR_(XI-15)R_(XI-16),

[0508] in which

[0509] R_(XI-15) and R_(XI-16) are identical or different and have themeaning given above for R_(XI-3) and R_(XI-4),

[0510] or

[0511] R_(XI-7) and R_(XI-8) together form a radical of the formula ═Oor ═NR_(XI-17), in which

[0512] R_(XI-17) denotes hydrogen or straight-chain or branched alkyl,alkoxy or acyl with up to 6 carbon atoms each,

[0513] L_(XI) denotes a straight-chain or branched alkylene- oralkenylene chain with up to 8 carbon atoms each, which is possiblysubstituted up to 2-fold by hydroxy,

[0514] T_(XI) and X_(XI) are identical or different and denote astraight-chain or branched alkylene chain with up to 8 carbon atoms,

[0515] or

[0516] T_(XI) and X_(XI) denotes a bond,

[0517] V_(XI) stands for an oxygen- or sulfur atom or for an —NR_(XI-18)group,

[0518] in which

[0519] R_(XI-18) denotes hydrogen or straight-chain or branched alkylwith up to 6 carbon atoms, or phenyl,

[0520] E_(XI) stands for cycloalkyl with 3 to 8 carbon atoms, or standsfor straight-chain or branched alkyl with up to 8 carbon atoms, which ispossibly substituted by cycloalkyl with 3 to 8 carbon atoms or hydroxy,or stands for phenyl, which is possibly substituted by halogen ortrifluoromethyl,

[0521] R_(XI-1) and R_(XI-2) together form a straight-chain or branchedalkylene chain with up to 7 carbon atoms, which must be substituted by acarbonyl group and/or by a radical of the formula

[0522] in which

[0523] a and b are identical or different and denote a number 1, 2 or 3

[0524] R_(XI-19) denotes hydrogen, cycloalkyl with 3 to 7 carbon atoms,straight-chain or branched silylalkyl with up to 8 carbon atoms, orstraight-chain or branched alkyl with up to 8 carbon atoms, which ispossibly substituted by hydroxy, straight-chain or branched alkoxy withup to 6 carbon atoms, or by phenyl, which itself can be substituted byhalogen, nitro, trifluoromethyl, trifluoromethoxy or by phenylsubstituted by phenyl or tetrazol, and alkyl is possibly substituted bya group of the formula —OR_(XI-22),

[0525] in which

[0526] R_(XI-22) denotes straight-chain or branched acyl with up to 4carbon atoms, or benzyl,

[0527] or

[0528] R_(XI-19) denotes straight-chain or branched acyl with up to 20carbon atoms or benzoyl, which is possibly substituted by halogen,trifluoromethyl, nitro or trifluoromethoxy, or denotes straight-chain orbranched fluoroacyl with up to 8 carbon atoms and 9 fluorine atoms,

[0529] R_(XI-20) and R_(XI-21) are identical or different, denotinghydrogen, phenyl or straight-chain or branched alkyl with up to 6 carbonatoms,

[0530] or

[0531] R_(XI-20) and R_(XI-21) together form a 3- to 6-memberedcarbocycle, and, possibly also geminally, the alkylene chain formed byR_(XI-1) and R_(XI-2), is possibly substituted up to 6-fold, identicalor different, by trifluoromethyl, hydroxy, nitrile, halogen, carboxyl,nitro, azido, cyano, cycloalkyl or cycloalkyloxy with 3 to 7 carbonatoms each, by straight-chain or branched alkoxycarbonyl, alkoxy oralkoxythio with up to 6 carbon atoms each, or by straight-chain orbranched alkyl with up to 6 carbon atoms, which itself is substituted upto 2-fold, identical or different. by hydroxyl, benzyloxy,trifluoromethyl, benzoyl, straight-chain or branched alkoxy, oxyacyl orcarboxyl with up to 4 carbon atoms each, and/or phenyl—which itself canbe substituted by halogen, trifluoromethyl or trifluoromethoxy, and/orthe alkylene chain formed by R_(XI-1) and R_(XI-2) is substituted, alsogeminally, possibly up to 5-fold, identical or different, by phenyl,benzoyl, thiophenyl or sulfobenzyl—which themselves are possiblysubstituted by halogen, trifluoromethyl, trifluoromethoxy or nitro,and/or the alkylene chain formed by R_(XI-1) and R_(XI-2) is possiblysubstituted by a radical of the formula

[0532] in which

[0533] c denotes a number 1, 2, 3 or 4,

[0534] d denotes a number 0 or 1,

[0535] R_(XI-23) and R_(XI-24) are identical or different and denotehydrogen, cycloalkyl with 3 to 6 carbon atoms, straight-chain orbranched alkyl with up to 6 carbon atoms, benzyl or phenyl, which ispossibly substituted up to 2-fold. identical or different, by halogen,trifluoromethyl, cyano, phenyl or nitro, and/or the alkylene chainformed by R_(XI-1) and R_(XI-2) is possibly substituted by aspiro-jointed radical of the formula

[0536] in which

[0537] W_(XI) denotes either an oxygen or a sulfur atom,

[0538] Y_(XI) and Y′_(XI) together form a 2- to 6-memberedstraight-chain or branched alkylene chain,

[0539] e is a number 1, 2, 3, 4, 5, 6 or 7,

[0540] f denotes a number 1 or 2,

[0541] R_(XI-25), R_(XI-26), R_(XI-27), R_(XI-28), R_(XI-29), R_(XI-30)and R_(XI-31) are identical or different and denote hydrogen,trifluoromethyl, phenyl, halogen, or straight-chain or branched alkyl oralkoxy with up to 6 carbon atoms each,

[0542] or

[0543] R_(XI-25) and R_(XI-26) or R_(XI-27) and R_(XI-28) together forma straight-chain or branched alkyl chain with up to 6 carbon atoms,

[0544] or

[0545] R_(XI-25) and R_(XI-26) or R_(XI-27) and R_(XI-28) together forma radical of the formula

[0546] in which

[0547] W_(XI) has the meaning given above,

[0548] g is a number 1, 2, 3, 4, 5, 6 or 7,

[0549] R_(XI-32) and R_(XI-33) together form a 3- to 7-memberedheterocycle that contains an oxygen—or sulfur atom or a group of theformula SO, SO₂ or —NR_(XI-34),

[0550] in which

[0551] R_(XI-34) denotes hydrogen, phenyl, benzyl, or straight-chain orbranched alkyl with up to 4 carbon atoms.

[0552] Compounds of Formula XI and their methods of manufacture aredisclosed in PCT Publication No. WO 9914174, which is incorporatedherein by reference in its entirety for all purposes.

[0553] Another class of CETP inhibitors that finds utility with thepresent invention consists of 2-aryl-substituted pyridines having theFormula (XII)

[0554] or pharmaceutically acceptable salts, enantiomers, orstereoisomers of said compounds,

[0555] in which

[0556]_(XII) and E_(XII) are identical or different and stand for arylwith 6 to 10 carbon atoms which is possibly substituted, up to 5-foldidentical or different, by halogen, hydroxy, trifluoromethyl,trifluoromethoxy, nitro or by straight-chain or branched alkyl, acyl,hydroxy alkyl or alkoxy with up to 7 carbon atoms each, or by a group ofthe formula —NR_(XII-1)R_(XII-2),

[0557] where

[0558] R_(XII-1) and R_(XII-2) are identical or different and are meantto be hydrogen, phenyl or straight-chain or branched alkyl with up to 6carbon atoms,

[0559] D_(XII) stands for straight-chain or branched alkyl with up to 8carbon atoms, which is substituted by hydroxy,

[0560] L_(XII) stands for cycloalkyl with 3 to 8 carbon atoms or forstraight-chain or branched alkyl with up to 8 carbon atoms, which ispossibly substituted by cycloalkyl with 3 to 8 carbon atoms, or byhydroxy,

[0561] T_(XII) stands for a radical of the formula R_(XII-3)—X_(XII)— or

[0562] where

[0563] R_(XII-3) and R_(XII-4) are identical or different and are meantto be cycloalkyl with 3 to 8 carbon atoms, or aryl with 6 to 10 carbonatoms, or a 5- to 7-membered aromatic, possibly benzocondensatedheterocycle with up to 3 heteroatoms from the series S, N and/or O,which are possibly substituted. up to 3-fold identical or different, bytrifluoromethyl, trifluoromethoxy, halogen, hydroxy, carboxyl, nitro, bystraight-chain or branched alkyl, acyl, alkoxy or alkoxycarbonyl with upto 6 carbon atoms each. or by phenyl, phenoxy or phenylthio which inturn can be substituted by halogen. trifluoromethyl or trifluoromethoxy,and/or where the cycles are possibly substituted by a group of theformula —NR_(XII-7)R_(XII-8),

[0564] where

[0565] R_(XII-7) and R_(XII-8) are identical or different and have themeaning of R_(XII-1) and R_(XII-2) given above,

[0566] X_(XII) is a straight-chain or branched alkyl or alkenyl with 2to 10 carbon atoms each, possibly substituted up to 2-fold by hydroxy orhalogen,

[0567] R_(XII-5) stands for hydrogen,

[0568] and

[0569] R_(XII-6) means to be hydrogen, halogen, mercapto, azido,trifluoromethyl, hydroxy, trifluoromethoxy, straight-chain or branchedalkoxy with up to 5 carbon atoms, or a radical of the formulaBNR_(XII-9)R_(XII-10),

[0570] where

[0571] R_(XII-9) and R_(XII-10) are identical or different and have themeaning of R_(XII-1) and R_(XII-2) given above,

[0572] or

[0573] R_(XII-5) and R_(XII-6), together with the carbon atom, form acarbonyl group.

[0574] Compounds of Formula XII and their methods of manufacture aredisclosed in EP 796846-A1, U.S. Pat. No. 6,127,383 and U.S. Pat. No.5,925,645, all of which are incorporated herein by reference in theirentireties for all purposes.

[0575] In a preferred embodiment, the CETP inhibitor is selected fromthe following compounds of Formula XII:

[0576]4,6-bis-(p-fluorophenyl)-2-isopropyl-3-[(p-trifluoromethylphenyl)-(fluoro)-methyl]-5-(1-hydroxyethyl)pyridine;

[0577]2,4-bis-(4-fluorophenyl)-6-isopropyl-5-[4-(trifluoromethylphenyl)-fluoromethyl]-3-hydroxymethyl)pyridine;and

[0578]2,4-bis-(4-fluorophenyl)-6-isopropyl-5-[2-(3-trifluoromethylphenyl)vinyl]-3-hydroxymethyl)pyridine.

[0579] Another class of CETP inhibitors that finds utility with thepresent invention consists of compounds having the Formula (XIII)

[0580] or pharmaceutically acceptable salts, enantiomers, stereoisomers,hydrates, or solvates of said compounds, in which

[0581] R_(XIII) is a straight chain or branched C₁₋₁₀ alkyl; straightchain or branched C₂₋₁₀ alkenyl; halogenated C₁₋₄ lower alkyl; C₃₋₁₀cycloalkyl that may be substituted; C₅₋₈ cycloalkenyl that may besubstituted; C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl that may be substituted; arylthat may be substituted; aralkyl that may be substituted; or a 5- or6-membered heterocyclic group having 1 to 3 nitrogen atoms, oxygen atomsor sulfur atoms that may be substituted,

[0582] X_(XIII-1), X_(XIII-2), X_(XIII-3), X_(XIII-4) may be the same ordifferent and are a hydrogen atom; halogen atom; C₁₋₄ lower alkyl;halogenated C₁₋₄ lower alkyl; C₁₋₄ lower alkoxy; cyano group; nitrogroup; acyl; or aryl, respectively;

[0583] Y_(XIII) is —CO—; or BSO₂—; and

[0584] Z_(XIII) is a hydrogen atom; or mercapto protective group.

[0585] Compounds of Formula XIII and their methods of manufacture aredisclosed in PCT Publication No. WO 98/35937, which is incorporatedherein by reference in its entirety for all purposes.

[0586] In a preferred embodiment, the CETP inhibitor is selected fromthe following compounds of Formula XIII:

[0587] N,N′-(dithiodi-2,1-phenylene)bis[2,2-dimethyl-propanamide];

[0588]N,N′-(dithiodi-2,1-phenylene)bis[1-methyl-cyclohexanecarboxamide];

[0589]N,N′-(dithiodi-2,1-phenylene)bis[1-(3-methylbutyl)-cyclopentanecarboxamide];

[0590]N,N′-(dithiodi-2,1-phenylene)bis[1-(3-methylbutyl)-cyclohexanecarboxamide];

[0591]N,N′-(dithiodi-2,1-phenylene)bis[1-(2-ethylbutyl)-cyclohexanecarboxamide];

[0592]N,N′-(dithiodi-2,1-phenylene)bis-tricyclo[3.3.1.1^(3,7)]decane-1-carboxamide;

[0593] propanethioic acid,2-methyl-,S-[2[[[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino]phenyl]ester;

[0594] propanethioic acid, 2,2-dimethyl-,S-[2-[[[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino]phenyl] ester; and

[0595] ethanethioic acid,S-[2-[[[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino]phenyl] ester.

[0596] Another class of CETP inhibitors that finds utility with thepresent invention consists of polycyclic aryl and heteroaryltertiary-heteroalkylamines having the Formula XIV

[0597] Formula XIV

[0598] and pharmaceutically acceptable forms thereof, wherein:

[0599] n_(XIV) is an integer selected from 0 through 5;

[0600] R_(XIV-1) is selected from the group consisting of haloalkyl,haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl;

[0601] X_(XIV) is selected from the group consisting of O, H, F, S,S(O),NH, N(OH), N(alkyl), and N(alkoxy);

[0602] R_(XIV-16) is selected from the group consisting of hydrido,alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl,alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl,heteroaralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl,haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl,haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl,halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl,perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, monocarboalkoxyalkyl,monocarboalkoxy, dicarboalkoxyalkyl, monocarboxamido, monocyanoalkyl,dicyanoalkyl, carboalkoxycyanoalkyl, acyl, aroyl, heteroaroyl,heteroaryloxyalkyl, dialkoxyphosphonoalkyl, trialkylsilyl, and a spacerselected from the group consisting of a covalent single bond and alinear spacer moiety having from 1 through 4 contiguous atoms linked tothe point of bonding of an aromatic substituent selected from the groupconsisting of R_(XIV-4), R_(XIV-8), R_(XIV-9), and R_(XIV-13) to form aheterocyclyl ring having from 5 through 10 contiguous members with theprovisos that said spacer moiety is other than a covalent single bondwhen R_(XIV-2) is alkyl and there is no R_(XIV-16) wherein X is H or F;

[0603] D_(XIV-1), D_(XIV-2), J_(XIV-1), J_(XIV-2) and K_(XIV-1) areindependently selected from the group consisting of C, N, O, S and acovalent bond with the provisos that no more than one of D_(XIV-1),D_(XIV-2), J_(XIV-1), J_(XIV-2) and K_(XIV-1) is a covalent bond, nomore than one of D_(XIV-1), D_(XIV-2), J_(XIV-1), J_(XIV-2) andK_(XIV-1) is 0, no more than one of D_(XIV-1), D_(XIV-2), J_(XIV-1),J_(XIV-2) and K_(XIV-1) is S, one of D_(XIV-1), D_(XIV-2) J_(XIV-1),J_(XIV-2) and K_(XIV-1) must be a covalent bond when two of D_(XIV-1),D_(XIV-2), J_(XIV-1), J_(XIV-2) and K_(XIV-1) are O and S, and no morethan four of D_(XIV-1), D_(XIV-2), J_(XIV-1), J_(XIV-) ₂ and K_(XIV-1)are N;

[0604] D_(XIV-3), D_(XIV-4) J_(XIV-3), J_(XIV-4) and K_(XIV-2) areindependently selected from the group consisting of C, N, O, S and acovalent bond with the provisos that no more than one of D_(XIV-3),D_(XIV-4), J_(XIV-3), J_(XIV-4) and K_(XIV-2) is a covalent bond, nomore than one of D_(XIV-3) D_(XIV-4), J_(XIV-3), J_(XIV-4) and K_(XIV-2)is O, no more than one of D_(XIV-3), D_(XIV-4), J_(XIV-3), J_(XlV-4) andK_(XIV-2) is S, one of D_(XIV-3), D_(XIV-4), J_(XIV-3), J_(XIV-4) andK_(XIV-2) must be a covalent bond when two of D_(XIV-3), D_(XIV-4),J_(XIV-3), J_(XIV-4) and K_(XIV-2) are O and S, and no more than four ofD_(XIV-3), D_(XIV-4), J_(XIV-3), J_(XIV-4) and K_(XIV-2) and K_(XIV)-₂are N;

[0605] R_(XIV-2) is independently selected from the group consisting ofhydrido, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylamino,dialkylamino, alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkoxyalkyl,aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl,alkylthioalkyl, aralkylthioalkyl, arylthioalkyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl,haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy,aloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl,heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl,dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl,alkylsulfinyl, alkylsulfonyl, alkylsulfinylalkyl, alkylsulfonylalkyl,haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl,arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl,cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl,cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl,heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl,aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide,carboxamidoalkyl, carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl;

[0606] R_(XIV-2) and R_(XIV-3) are taken together to form a linearspacer moiety selected from the group consisting of a covalent singlebond and a moiety having from 1 through 6 contiguous atoms to form aring selected from the group consisting of a cycloalkyl having from 3through 8 contiguous members, a cycloalkenyl having from 5 through 8contiguous members, and a heterocyclyl having from 4 through 8contiguous members;

[0607] R_(XIV-3) is selected from the group consisting of hydrido,hydroxy, halo, cyano, aryloxy, hydroxyalkyl, amino, alkylamino,dialkylamino, acyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio,alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl,heteroarylthio, aralkylthio, aralkoxyalkyl, alkylsulfinylalkyl,alkylsulfonylalkyl, aroyl, heteroaroyl, aralkylthioalkyl,heteroaralkylthioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl,alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl,haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy,haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl,heteroarylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl,monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl,alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl,arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl,aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl,cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl,carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl;

[0608] Y_(XIV) is selected from a group consisting of a covalent singlebond,(C(R_(XIV-14))₂)_(qXIV) wherein _(qXIV) is an integer selected from1 and 2 and (CH(R_(XIV-14)))_(gXIV)—W_(XIV)-(CH(R_(XIV-14)))_(pXIV)wherein _(gXIV) and _(pXIV) are integers independently selected from 0and 1;

[0609] R_(XIV-14) is independently selected from the group consisting ofhydrido, hydroxy, halo, cyano, aryloxy, amino, alkylamino, dialkylamino,hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl,acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl,aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkylsulfinylalkyl,alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl,alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl,arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl,cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl,heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl,monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl,haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl,arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl,carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected froma moiety having a chain length of 3 to 6 atoms connected to the point ofbonding selected from the group consisting of R_(XIV-9) and R_(XIV-13)to form a ring selected from the group consisting of a cycloalkenyl ringhaving from 5 through 8 contiguous members and a heterocyclyl ringhaving from 5 through 8 contiguous members and a spacer selected from amoiety having a chain length of 2 to 5 atoms connected to the point ofbonding selected from the group consisting of R_(XIV-4) and R_(XIV-8) toform a heterocyclyl having from 5 through 8 contiguous members with theproviso that, when Y_(XIV) is a covalent bond, an R_(XIV-14) substituentis not attached to Y_(XIV);

[0610] R_(XIV-14) and R_(XIV-14), when bonded to the different atoms,are taken together to form a group selected from the group consisting ofa covalent bond, alkylene, haloalkylene, and a spacer selected from agroup consisting of a moiety having a chain length of 2 to 5 atomsconnected to form a ring selected from the group of a saturatedcycloalkyl having from 5 through 8 contiguous members, a cycloalkenylhaving from 5 through 8 contiguous members, and a heterocyclyl havingfrom 5 through 8 contiguous members;

[0611] R_(XIV-14) and R_(XIV-14), when bonded to the same atom are takentogether to form a group selected from the group consisting of oxo,thiono, alkylene, haloalkylene, and a spacer selected from the groupconsisting of a moiety having a chain length of 3 to 7 atoms connectedto form a ring selected from the group consisting of a cycloalkyl havingfrom 4 through 8 contiguous members, a cycloalkenyl having from 4through 8 contiguous members, and a heterocyclyl having from 4 through 8contiguous members;

[0612] W_(XIV) is selected from the group consisting of O, C(O), C(S),C(O)N(R_(XIV-14)), C(S)N(R_(XIV-14)), (R_(XIV-14))NC(O),(R_(XIV-14))NC(S), S, S(O), S(O)₂, S(O)₂N(R_(XIV-14)),(R_(XIV-14))NS(O)₂, and N(R_(XIV-14)) with the proviso that R_(XIV-14)is selected from other than halo and cyano;

[0613] Z_(XIV) is independently selected from a group consisting of acovalent single bond, (C(R_(XIV-15))₂)_(qXIV-2) wherein _(qXIV-2) is aninteger selected from 1 and 2,(CH(R_(XIV-15)))_(jXIV)—W—(CH(R_(XIV-15)))_(kXIV) wherein _(jXIV) and_(kXIV) are integers independently selected from 0 and 1 with theproviso that, when Z_(XIV) is a covalent single bond, an R_(XIV-15)substituent is not attached to Z_(XIV);

[0614] R_(XIV-15) is independently selected, when Z_(XIV) is(C(R_(XIV-15))₂)_(qXIV) wherein _(qXIV) is an integer selected from 1and 2, from the group consisting of hydrido, hydroxy, halo, cyano,aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, acyl, aroyl,heteroaroyl, heteroaryloxyalkyl, sulfhydryl, acylamido, alkoxy,alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl,aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl,aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl,heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl,cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl,cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl,heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl,monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl,haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl,arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl,

[0615] heteroarylsulfonyl, heteroarylsulfinylalkyl,aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl,carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy,dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl,diaralkoxyphosphonoalkyl, a spacer selected from a moiety having a chainlength of 3 to 6 atoms connected to the point of bonding selected fromthe group consisting of R_(XIV-4) and R_(XIV-8) to form a ring selectedfrom the

[0616] group consisting of a cycloalkenyl ring having from 5 through 8contiguous members and a heterocyclyl ring having from 5 through 8contiguous members, and a spacer selected from a moiety having a chainlength of 2 to 5 atoms connected to the point of bonding selected fromthe group consisting of R_(XIV-9) and R_(XIV-13) to form a heterocyclylhaving from 5 through 8 contiguous members;

[0617] R_(XIV-15) and R_(XIV-15), when bonded to the different atoms,are taken together to form a group selected from the group consisting ofa covalent bond, alkylene, haloalkylene, and a spacer selected from agroup consisting of a moiety having a chain length of 2 to 5 atomsconnected to form a ring selected from the group of a saturatedcycloalkyl having from 5 through 8 contiguous members, a cycloalkenylhaving from 5 through 8 contiguous members, and a heterocyclyl havingfrom 5 through 8 contiguous members;

[0618] R_(XIV-15) and R_(XIV-15), when bonded to the same atom are takentogether to form a group selected from the group consisting of oxo,thiono, alkylene, haloalkylene, and a spacer selected from the groupconsisting of a moiety having a chain length of 3 to 7 atoms connectedto form a ring selected from the group consisting of a cycloalkyl havingfrom 4 through 8 contiguous members, a cycloalkenyl having from 4through 8 contiguous members, and a heterocyclyl having from 4 through 8contiguous members;

[0619] R_(XIV-15) is independently selected, when Z_(XIV) is(CH(R_(XIV-15)))_(jXIV)—W—(CH(R_(XIV-15)))_(kXIV) wherein _(jXIV) and_(kXIV) are integers independently selected from 0 and 1, from the groupconsisting of hydrido, halo, cyano, aryloxy, carboxyl, acyl, aroyl,heteroaroyl, hydroxyalkyl, heteroaryloxyalkyl, acylamido, alkoxy,alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl,aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, aralkoxyalkyl,heteroaralkoxyalkyl, alkylsulfonylalkyl, alkylsulfinylalkyl,alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl,haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy,haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl,heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl,dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl,alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl,arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl,aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy,dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected froma linear moiety having a chain length of 3 to 6 atoms connected to thepoint of bonding selected from the group consisting of R_(XIV-4) andR_(XIV-8) to form a ring selected from the group consisting of acycloalkenyl ring having from 5 through 8 contiguous members and aheterocyclyl ring having from 5 through 8 contiguous members, and aspacer selected from a linear moiety having a chain length of 2 to 5atoms connected to the point of bonding selected from the groupconsisting of R_(XIV-9) and R_(XIV-13) to form a heterocyclyl ringhaving from 5 through 8 contiguous members;

[0620] R_(XIV-4), R_(XIV-5), R_(XIV-6), R_(XIV-7), R_(XIV-8), R_(XIV-9),R_(XIV-10), R_(XIV-11), R_(XIV-12), and R_(XIV-13) are independentlyselected from the group consisting of perhaloaryloxy, alkanoylalkyl,alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy,heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy,alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy,aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido,N-cycloalkylcarboxamido, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl,cyanoalkoxy, heterocyclylcarbonyl, hydrido, carboxy, heteroaralkylthio,heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy,heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl,heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl,aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl,cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl,cycloalkylsulfonylalkyl, heteroarylamino,N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio,alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy,cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy,cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl,hydroxy, amino, thio, nitro, lower alkylamino, alkylthio,alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl,heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl,arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl,heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl, dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl,arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl,heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl,heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl,alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy,cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl,lower cycloalkenylalkyl, halo, haloalkyl; haloalkenyl, haloalkoxy,hydroxyhaloalkyl, hydroxyaralkyl, hydroxyaikyl, hydoxyheteroaralkyl,haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl,saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl,carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl,carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy,phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl with the proviso that there are one to fivenon-hydrido ring substituents R_(XIV-4), R_(XlV-5), R_(XIV-6), R_(XIV-7)and R_(XIV-8) present, that there are one to five non-hydrido ringsubstituents R_(XIV-9), R_(XIV-10), R_(XIV-11), R_(XIV-12), andR_(XIV-13) present, and R_(XIV-4), R_(XIV-5), R_(XIV-6), R_(XIV-7),R_(XIV-8), R_(XIV-9), R_(XIV-10), R_(XIV-11), R_(XIV-12), and R_(XIV-13)are each independently selected to maintain the tetravalent nature ofcarbon, trivalent nature of nitrogen, the divalent nature of sulfur, andthe divalent nature of oxygen;

[0621] R_(XIV-4) and R_(XIV-5), R_(XIV-5) and R_(XIV-6), R_(XIV-6) andR_(XIV-7), R_(XIV-7) and R_(XIV-8), R_(XIV-8) and R_(XIV-9), R_(XIV-9)and R_(XIV-10), R_(XIV-10) and R_(XIV-11), R_(XIV-11) and R_(XIV-12),and R_(XIV-12) and R_(XIV-13) are independently selected to form spacerpairs wherein a spacer pair is taken together to form a linear moietyhaving from 3 through 6 contiguous atoms connecting the points ofbonding of said spacer pair members to form a ring selected from thegroup consisting of a cycloalkenyl ring having 5 through 8 contiguousmembers, a partially saturated heterocyclyl ring having 5 through 8contiguous members, a heteroaryl ring having 5 through 6 contiguousmembers, and an aryl with the provisos that no more than one of thegroup consisting of spacer pairs R_(XIV-4) and R_(XIV-5), R_(XIV-5) andR_(XIV-6), R_(XIV-6) and R_(XIV-7), and R_(XIV-7) and R_(XIV-8) are usedat the same time and that no more than one of the group consisting ofspacer pairs R_(XIV-9) and R_(XIV-10), R_(XIV-10) and R_(XIV-11),R_(XIV-11) and R_(XIV-12), and R_(XIV-12) and R_(XIV-13) are used at thesame time;

[0622] R_(XIV-4) and R_(XIV-9), R_(XIV-4) and R_(XIV-13), R_(XIV-8) andR_(XIV-9), and R_(XIV-8) and R_(XIV-13) are independently selected toform a spacer pair wherein said spacer pair is taken together to form alinear moiety wherein said linear moiety forms a ring selected from thegroup consisting of a partially saturated heterocyclyl ring having from5 through 8 contiguous members and a heteroaryl ring having from 5through 6 contiguous members with the proviso that no more than one ofthe group consisting of spacer pairs R_(XIV-4) and R_(XIV-9), R_(XIV-4)and R_(XIV-13), R_(XIV-8) and R_(XIV-9), and R_(XIV-8) and R_(XIV-13) isused at the same time.

[0623] Compounds of Formula XIV and their methods of manufacture aredisclosed in PCT Publication No. WO 00/18721, which is incorporatedherein by reference in its entirety for all purposes.

[0624] In a preferred embodiment, the CETP inhibitor is selected fromthe following compounds of Formula XIV:

[0625]3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0626]3-[[3-(3-isopropylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0627]3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0628]3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]1,1,1-trifluoro-2-propanol;

[0629]3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0630]3-[[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0631]3-[[3-(4-methlylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0632]3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0633]3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0634] 3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0635]3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0636]3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0637]3-[[3-(3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0638]3-[[3-(3-t-butylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]1,1,1-trifluoro-2-propanol;

[0639]3-[[3-(3-methylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0640]3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0641] 3-[[3-(phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0642]3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0643]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethoxy)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0644]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethyl)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0645]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,11 -trifluoro-2-propanol;

[0646]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,-trifluoro-2-propanol;

[0647]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0648]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0649]3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0650]3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0651]3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0652]3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0653]3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1,-trifluoro-2-propanol;

[0654]3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(pentafluoroethymethyl]amino]-1,1,1-trifluoro-2-propanol;

[0655] 3-[[³-(³-isopropylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0656] 3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0657] 3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0658] 3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0659] 3-[[3-(4-fluorophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1 -trifluoro-2-propanol;

[0660] 3-[[3-(4-methylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0661] 3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0662] 3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0663]3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(pentafluoroethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0664]3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0665] 3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1 -trifluoro-2-propanol;

[0666] 3-[[3-(3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0667] 3-[[3-(3-t-butylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1 -trifluoro-2-propanol;

[0668] 3-[[3-(3-methylphenoxy)phenyl][[3-pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0669]3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0670]3-[[³-(phenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0671]3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0672]3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0673]3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0674]3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0675]3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0676]3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3,5-difluorophenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0677] 3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[cyclohexylmethoxy,phenyl]-amino]-1,1,1-trifluoro-2-propanol;

[0678]3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0679]3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0680] 3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0681]3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0682]3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(pentafluoroethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0683]3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0684] 3-[[3-(3-isopropylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0685] 3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0686] 3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0687] 3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0688] 3-[[3-(4-fluorophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0689] 3-[[3-(4-methylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0690] 3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifiuoro-2-propanol;

[0691] 3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0692]3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(heptafluoropropyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0693]3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0694] 3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0695] 3-[[3-(3-ethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0696] 3-[[3-(3-t-butylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0697] 3-[[3-(3-methylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0698]3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0699]3-[[3-(phenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0700]3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0701]3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0702]3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0703]3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3,5-dimethylphenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0704]3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0705]3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3,5-difluorophenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0706]3-[[[³-(heptafluoropropyl)phenyl]methyl][3-[cyclohexylmethoxy]phenyl]-amino]-1,1,1-trifluoro-2-propanol;

[0707]3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0708]3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0709] 3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0710]3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0711]3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(heptafluoropropyl)-phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0712]3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0713]3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0714]3-[[3-(3-cyclopropylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0715]3-[[3-(3-(2-furyl)phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0716]3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0717] 3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0718]3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0719]3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0720]3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0721]3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[2-fluoro-5-(trifluoro-methyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0722]3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0723]3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0724] 3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0725] 3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0726] 3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0727]3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0728] 3-[[3-(phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0729]3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0730]3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0731]3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethyl)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0732]3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-11,1 -trifluoro-2-propanol;

[0733]3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0734]3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0735]3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0736]3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0737]3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0738]3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0739]3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0740]3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0741]3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0742]3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0743]3-[[3-(3-cyclopropylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0744]3-[[3-(3-(2-furyl)phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0745]3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0746] 3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0747] 3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0748]3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0749]3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0750]3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[2-fluoro-4-(trifluoro-methyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0751]3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0752]3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0753] 3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0754] 3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0755] 3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0756]3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0757] 3-[[3-(phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0758]3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0759]3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0760]3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethyl)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0761] 3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0762]3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0763]3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0764]3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0765]3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0766]3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0767]3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0768]3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;and

[0769]3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-4-(trifluoro-methyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol.

[0770] Another class of CETP inhibitors that finds utility with thepresent invention consists of substitued N-Aliphatic-N-Aromatictertiary-Heteroalkylamines having the Formula XV

[0771] Formula XV

[0772] and pharmaceutically acceptable forms thereof, wherein:

[0773] n_(XV) is an integer selected from 1 through 2;

[0774] A_(XV) and Q_(XV) are independently selected from the groupconsisting of—CH₂(CR_(XV-37)R_(XV-38))_(vXV)-(CR_(XV-33)R_(XV-34))_(uXV)-T_(XV)-(CR_(XV-35)R_(XV-36))_(wXV-)H,

[0775] with the provisos that one of A_(XV) and Q_(XV) must be AQ-1 andthat one of A_(XV) and Q_(XV) must be selected from the group consistingof AQ-2 and—CH₂(CR_(XV-37)R_(XV-38))_(vXV)—(CR_(XV-33)R_(XV-34))_(uXV)-T_(XV)-(CR_(XV-35)R_(XV-36))_(wXV)—H;

[0776] T_(XV) is selected from the group consisting of a single covalentbond, O, S, S(O), S(O)₂, C(R_(XV-33))═C(R_(XV-35)) and

[0777] v_(XV) is an integer selected from 0 through 1 with the provisothat _(vXV) is 1 when any one of R_(XV-33), R_(XV-34), R_(XV-35), andR_(XV-36) is aryl or heteroaryl;

[0778]_(uXV) and _(wXV) are integers independently selected from 0through 6;

[0779] A_(XV-1) is C(R_(XV-30));

[0780] D_(XV-1), D_(XV-2), J_(XV-1), J_(XV-2), and K_(XV-1) areindependently selected from the group consisting of C, N, O, S and acovalent bond with the provisos that no more than one of D_(XV-1),D_(XV-2), J_(XV-1), J_(XV-2), and K_(XV-1) is a covalent bond, no morethan one of D_(XV-1), D_(XV-2), J_(XV-1), J_(XV-2), and K_(XV-1) is O,nomore than one of D_(XV-1), D_(XV-2), J_(XV-1), J_(XV-2), and K_(XV-1) isS, one of D_(XV-1), D_(XV-2), J_(XV-1), J_(XV-2), and K_(XV-1) must be acovalent bond when two of D_(XV-1), D_(XV-2), J_(XV-1), J_(XV-2), andK_(XV-1) are O and S, and no more than four of D_(XV-1), D_(XV-2),J_(XV-1), J_(XV-2), and K_(XV-1) are N;

[0781] B_(XV-1), B_(XV-2), D_(XV-3), D_(XV-4), J_(XV-3), J_(XV-4), andK_(XV-2) are independently selected from the group consisting of C,C(R_(XV-30)), N, O, S and a covalent bond with the provisos that no morethan 5 of B_(XV-1), B_(XV-2), D_(XV-3), D_(XV-4), J_(XV-3), J_(XV-4),and K_(XV-2) are a covalent bond, no more than two of B_(XV-1),B_(XV-2), D_(XV-3), D_(XV-4), J_(XV-3), J_(XV-4), and K_(XV-2) are O, nomore than two of B_(XV-1), B_(XV-2), D_(XV-3), D_(XV-4), J_(XV-3),J_(XV-4), and K_(XV-2) are S, no more than two of B_(XV-1), B_(XV-2),D_(XV-3), D_(XV-4), J_(XV-3), J_(XV-4), and K_(XV-2) are simultaneouslyO and S, and no more than two of B_(XV-1), B_(XV-2), D_(XV-3), D_(XV-4),J_(XV-3), J_(XV-4), and K_(XV-2) are N;

[0782] B_(XV-1) and D_(XV-3), D_(XV-3) and J_(XV-3), J_(XV-3) andK_(XV-2), K_(XV-2) and J_(XV-4), J_(XV-4) and D_(XV-4), and D_(XV-4) andB_(XV-2) are independently selected to form an in-ring spacer pairwherein said

[0783] spacer pair is selected from the group consisting ofC(R_(XV-33))═C(R_(XV-35)) and N═N with the provisos that AQ-2 must be aring of at least five contiguous members, that no more than two of thegroup of said spacer pairs are simultaneously C(R_(XV-33))═C(R_(XV-35))and that no more than one of the group of said spacer pairs can be N═Nunless the other spacer pairs are other than C(R_(XV-33))═C(R_(XV-35)),O, N, and S;

[0784] R_(XV-1) is selected from the group consisting of haloalkyl andhaloalkoxymethyl;

[0785] R_(XV-2) is selected from the group consisting of hydrido, aryl,alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl and heteroaryl;

[0786] R_(XV-3) is selected from the group consisting of hydrido, aryl,alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl;

[0787] Y_(XV) is selected from the group consisting of a covalent singlebond, (CH₂)_(q) wherein q is an integer selected from 1 through 2 and(CH₂)_(j)—O—(CH₂)_(k) wherein j and k are integers independentlyselected from 0 through 1;

[0788] Z_(XV) is selected from the group consisting of covalent singlebond, (CH₂)_(q) wherein q is an integer selected from 1 through 2, and(CH₂)_(j)—O—(CH₂)_(k) wherein j and k are integers independentlyselected from 0 through 1;

[0789] R_(xv-4), R_(xv-8), R_(xv-9) and R_(xv-13) are independentlyselected from the group consisting of hydrido, halo, haloalkyl, andalkyl;

[0790] R_(XV-30) is selected from the group consisting of hydrido,alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio,alkylthioalkyl, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl with theproviso that R_(xv-30) is selected to maintain the tetravalent nature ofcarbon, trivalent nature of nitrogen, the divalent nature of sulfur, andthe divalent nature of oxygen;

[0791] R_(XV-30), when bonded to A_(XV-1), is taken together to form anintra-ring linear spacer connecting the A_(XV-1)-carbon at the point ofattachment of R_(XV-30) to the point of bonding of a group selected fromthe group consisting of R_(XV-10), R_(XV-11), R_(XV-12), R_(XV-31), andR_(XV-32) wherein said intra-ring linear spacer is selected from thegroup consisting of a covalent single bond and a spacer moiety havingfrom 1 through 6 contiguous atoms to form a ring selected from the groupconsisting of a cycloalkyl having from 3 through 10 contiguous members,a cycloalkenyl having from 5 through 10 contiguous members, and aheterocyclyl having from 5 through 10 contiguous members;

[0792] R_(XV-30), when bonded to A_(XV-1), is taken together to form anintra-ring branched spacer connecting the A_(XV-1)-carbon at the pointof attachment of R_(XV-30) to the points of bonding of each member ofany one of substituent pairs selected from the group consisting ofsubsitituent pairs R_(XV-10) and R_(XV-11), R_(XV-10) and R_(XV-31),R_(XV-10) and R_(XV-32), R_(XV-10) and R_(XV-12), R_(XV-11) andR_(XV-31), R_(XV-11) and R_(XV-32), R_(XV-11) and R_(XV-12), R_(XV-31)and R_(XV-32), R_(XV-31) and R_(XV-12), and R_(XV-32) and R_(XV-12) andwherein said intra-ring branched spacer is selected to form two ringsselected from the group consisting of cycloalkyl having from 3 through10 contiguous members, cycloalkenyl having from 5 through 10 contiguousmembers, and heterocyclyl having from 5 through 10 contiguous members;

[0793] R_(XV-4), R_(XV-5), R_(XV-6), R_(XV-7), R_(XV-8), R_(XV-9),R_(XV-10), R_(XV-11), R_(XV-12), R_(XV-13), R_(XV-31), R_(XV-32),R_(XV-33), R_(XV-34), R_(XV-35), and R_(XV-36) are independentlyselected from the group consisting of hydrido, carboxy,heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl,acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl,aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl,aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl,halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl,cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl,heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl,haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl,heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl,cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy,halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy,halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino,alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio,arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl,arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl,heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl, dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl,arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl,heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl,heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl,alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy,cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl,lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy,hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl,haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl,saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl,carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,alkylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl,carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy,phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl with the provisos that R_(XV-4), R_(XV-5),R_(XV-6), R_(XV-7), R_(XV-8), R_(XV-9), R_(XV-10), R_(XV-11), R_(XV-12),R_(XV-13), R_(XV-31), R_(XV-32), R_(XV-33), R_(XV-34), R_(XV-35), andR_(XV-36) are each independently selected to maintain the tetravalentnature of carbon, trivalent nature of nitrogen, the divalent nature ofsulfur, and the divalent nature of oxygen, that no more than three ofthe R_(XV-33) and R_(XV-34) substituents are simultaneously selectedfrom other than the group consisting of hydrido and halo, and that nomore than three of the R_(XV-35) and R_(XV-36) substituents aresimultaneously selected from other than the group consisting of hydridoand halo;

[0794] R_(XV-9), R_(XV-10), R_(XV-11), R_(XV-12), R_(XV-13), R_(XV-31),and R_(XV-32) are independently selected to be oxo with the provisosthat B_(XV-1), D_(XV-2), D_(XV-3), D_(XV-4), J_(XV-3), J_(XV-4), andK_(XV-2) are independently selected from the group consisting of C andS, no more than two of R_(XV-9), R_(XV-10), R_(XV-11), R_(XV-12),R_(XV-13), R_(XV-31), and R_(XV-32) are simultaneously oxo, and thatR_(XV-9), R_(XV-10), R_(XV-11), R_(XV-12), R_(XV-13), R_(XV-31), andR_(XV-32) are each independently selected to maintain the tetravalentnature of carbon, trivalent nature of nitrogen, the divalent nature ofsulfur, and the divalent nature of oxygen;

[0795] R_(XV-4) and R_(XV-5), R_(XV-5) and R_(XV-6), R_(XV-6) andR_(XV-7), R_(XV-7) and R_(XV-8), R_(XV-9) and R_(XV-10), R_(XV-10) andR_(XV-11), R_(XV-11) and R_(XV-31), R_(XV-31) and R_(XV-32), R_(XV-32)and R_(XV-12), and R_(XV-12) and R_(XV-13) are independently selected toform spacer pairs wherein a spacer pair is taken together to form alinear moiety having from 3 through 6 contiguous atoms connecting thepoints of bonding of said spacer pair members to form a ring selectedfrom the group consisting of a cycloalkenyl ring having 5 through 8contiguous members, a partially saturated heterocyclyl ring having 5through 8 contiguous members, a heteroaryl ring having 5 through 6contiguous members, and an aryl with the provisos that no more than oneof the group consisting of spacer pairs R_(XV-4) and R_(XV-5), R_(XV-5)and R_(XV-6), R_(XV-6) and R_(XV-7), R_(XV-7) and R_(XV-8) is used atthe same time and that no more than one of the group consisting ofspacer pairs R_(XV-9) and R_(XV-1), R_(XV-10) and R_(XV-11), R_(XV-11)and R_(XV-31), R_(XV-31) and R_(XV-32), R_(XV-32) and R_(XV-12), andR_(XV-12) and R_(XV-13) are used at the same time;

[0796] R_(XV-9) and R_(XV-11), R_(XV-9) and R_(XV-12), R_(XV-9) andR_(XV-13) R_(XV-9) and R_(XV-31), R_(XV-9) and R_(XV-32), R_(XV-10) andR_(XV-12), R_(XV-10) and R_(XV-13), R_(XV-10) and R_(XV-31), R_(XV-10)and R_(XV-32), R_(XV-11) and R_(XV-12), R_(XV-11) and R_(XV-13),R_(XV-11) and R_(XV-32), R_(XV-12) and R_(XV-31), R_(XV-13) andR_(XV-31), and R_(XV-13) and R_(XV-32) are independently selected toform a spacer pair wherein said spacer pair is taken together to form alinear spacer moiety selected from the group consisting of a covalentsingle bond and a moiety having from 1 through 3 contiguous atoms toform a ring selected from the group consisting of a cycloalkyl havingfrom 3 through 8 contiguous members, a cycloalkenyl having from 5through 8 contiguous members, a saturated heterocyclyl having from 5through 8 contiguous members and a partially saturated heterocyclylhaving from 5 through 8 contiguous members with the provisos that nomore than one of said group of spacer pairs is used at the same time;

[0797] R_(XV-37) and R_(XV-38) are independently selected from the groupconsisting of hydrido, alkoxy, alkoxyalkyl, hydroxy, amino, thio, halo,haloalkyl, alkylamino, alkylthio, alkylthioalkyl, cyano, alkyl, alkenyl,haloalkoxy, and haloalkoxyalkyl.

[0798] Compounds of Formula XV and their methods of manufacture aredisclosed in PCT Publication No. WO 00/18723, which is incorporatedherein by reference in its entirety for all purposes.

[0799] In a preferred embodiment, the CETP inhibitor is selected fromthe following compounds of Formula XV:

[0800]3-[[3-(4-chloro-3-ethylphenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0801]3-[[3-(4-chloro-3-ethylphenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0802]3-[[3-(4-chloro-3-ethylphenoxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0803]3-[[3-(4-chloro-3-ethylphenoxy)phenyl][(3-trifiuoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0804] 3-[[3-(4-chloro-3-ethylphenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0805] 3-[[3-(4-chloro-3-ethylphenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0806]3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)cyclo-hexylmethyl]amino]-1,1,1-trifluoro-2-propanol;

[0807]3-[[3-(3-trifluoromethoxyphenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0808]3-[[3-(3-trifluoromethoxyphenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0809]3-[[3-(3-trifluoromethoxyphenoxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0810]3-[[3-(3-trifluoromethoxyphenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0811]3-[[3-(3-trifluoromethoxyphenoxy)phenyl]](3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0812]3-[[3-(3-trifluoromethoxyphenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0813]3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0814]3-[[3-(3-isopropylphenoxy)phenyl](cyclohexylmethyl]amino]-1,1,1-trifiuoro-2-propanol:

[0815]3-[[3-(3-isopropylphenoxy)phenyl](cyclopentylmethyl]amino]-1,1,1-trifluoro-2-propanol;

[0816]3-[[3-(3-isopropylphenoxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0817] 3-[[3-(3-isopropylphenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0818] 3-[[3-(3-isopropylphenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0819] 3-[[3-(3-isopropylphenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0820]3-[[3-(3-isopropylphenoxy)phenyl][3-(1,1,2,2-tetrafluoroethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0821]3-[[3-(2,3-dichlorophenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0822] 3-[[3-(2,3-dichlorophenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0823]3-[[3-(2,3-dichlorophenoxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0824] 3-[[3-(2,3-dichlorophenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0825] 3-[[3-(2,3-dichlorophenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0826] 3-[[3-(2,3-dichlorophenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0827]3-[[3-(2,3-dichlorophenoxy)phenyl][3-(1,1,2,2-tetrafluoroethoxy)cyclo-hexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0828]3-[[3-(4-fluorophenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0829] 3-[[3-(4-fluorophenoxy)phenyl](cyclopentylmethyl)amino]-1,11-trifluoro-2-propanol;

[0830]3-[[3-(4-fluorophenoxy)phenyl](cyclopropylmethyl)amino]-1,1,1-triflouro-2-propanol;

[0831] 3-[[3-(4-fluorophenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0832] 3-[[3-(4-fluorophenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0833] 3-[[3-(4-fluorophenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0834]3-[[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0835]3-[[3-(3-trifluoromethoxybenzyloxy]phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0836]3-[[3-(3-trifluoromethoxybenzyloxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0837]3-[[3-(3-trifluoromethoxybenzyloxy)phenyl](cyclopropylmethyl]amino]-1,1,1-trifluoro-2-propanol;

[0838]3-[[3-(3-trifluoromethoxybenzyloxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0839]3-[[3-(3-trifluoromethoxybenzyloxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0840]3-[[3-(3-trifluoromethoxybenzyloxy]phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0841]3-[[3-(3-trifluoromethoxybenzyloxy)phenyl][3-(1,1,2,2-tetrafluoroethoxy)-cyclohexylmethyl]amino]-1,1,1-trifluoro-2-propanol;

[0842]3-[[3-(3-trifluoromethylbenzyloxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0843]3-[[3-(3-trifluoromethylbenzyloxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0844]3-[[3-(3-trifluoromethylbenzyloxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0845]3-[[3-(3-trifluoromethylbenzyloxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0846]3-[[3-(3-trifluoromethylbenzyloxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0847]3-[[3-(3-trifluoromethylbenzyloxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0848]3-[[3-(3-trifluoromethylbenzyloxy)phenyl][3-(1,1,2,2-tetrafluoroethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0849]3-[[[(3-trifluoromethyl)phenyl]methyl](cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0850]3-[[[(3-pentafluoroethyl)phenyl]methyl](cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0851]3-[[[(3-trifluoromethoxy)phenyl]methyl](cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0852]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0853]3-[[[(3-trifluoromethyl)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0854]3-[[[(3-pentafluoroethyl)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0855]3-[[[(3-trifluoromethoxy)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0856]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0857]3-[[[(3-trifluoromethyl]phenyl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0858]3-[[[(3-pentafluoroethyl)phenyl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0859]3-[[[(3-trifluoromethoxy)phenyl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0860]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0861]3-[[[(3-trifluoromethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;

[0862]3-[[[(3-pentafluoroethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)cyclo-hexyl]amino]-1,1,1trifluoro-2-propanol;

[0863]3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(4-chloro-3-methylphenoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;

[0864]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-cyclohexyl]amino]-1,1,1-trifluoro-2-propanol;

[0865]3-[[[(3-trifluoromethyl]phenyl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0866]3-[[[(3-pentafluoroethyl)phenyl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0867]3-[[[(3-trifluoromethoxy)phenyl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0868]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0869]3-[[[(3-trifloromethyl)phenyl]methyl](3-isopropoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0870]3-[[[(3-pentafluoroethyl)phenyl]methyl](3-isopropoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0871]3-[[[(3-trifluoromethoxy)phenyl]methyl](3-isopropoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0872]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-isopropoxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;

[0873]3-[[[(3-trifluoromethyl)phenyl]methyl](3-cyclopentyloxycyclohexyl]amino]-1,1,1-trifluoro-2-propanol;

[0874]3-[[[(3-pentafluoroethyl]phenyl]methyl](3-cyclopentyloxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0875]3-[[[(3-trifluoromethoxy)phenyl]methyl](3-cyclopentyloxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0876]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-cyclopentyloxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;

[0877]3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-isopropoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0878]3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-cyclopentyloxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;

[0879]3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0880] 3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0881]3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl][3-(4-chloro-3-ethylphenoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;

[0882]3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl][3-(1,1,2,2-tetrafluoroethoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;

[0883]3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-pentafluoroethylcyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;

[0884]3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-trifluoromethoxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;

[0885]3-[[[(3-trifluoromethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)propyl]-amino]-1,1,1-trifluoro-2-propanol;

[0886]3-[[[(3-pentafluoroethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)propyl]-amino]-1,1,1-trifluoro-2-propanol;

[0887]3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)propyl]-amino]-1,1,1-trifluoro-2-propanol;

[0888]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-propyl]amino]-1,1,1-trifluoro-2-propanol;

[0889]3-[[[(3-trifluoromethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2,-di-fluropropyl]amino]-1,1,1-trifluoro-2-propanol;

[0890]3-[[[(3-pentafluoroethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2-di-fluropropyl]amino]-1,1,1-trifluoro-2-propanol;

[0891]3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2,-di-fluropropyl]amino]-1,1,1-trifluoro-2-propanol;

[0892]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2,-difluropropyl]amino]-1,1,1-trifluoro-2-propanol;

[0893]3-[[[(3-trifluoromethyl)phenyl]methyl][3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol;

[0894]3-[[[(3-pentafluoroethyl)phenyl]methyl][3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol;

[0895]3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol;

[0896]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]]3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol;and

[0897]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(phenoxy)propyl]amino]-1,1,1-trifluoro-2-propanol.

[0898] Another class of CETP inhibitors that finds utility with thepresent invention consists of (R)-chiral halogenated 1-substitutedamino-(n+1)-alkanols having the Formula XVI

[0899] and pharmaceutically acceptable forms thereof, wherein:

[0900] n_(XVI) is an integer selected from 1 through 4;

[0901] X_(XVI) is oxy;

[0902] R_(XVI-1) is selected from the group consisting of haloalkyl,haloalkenyl, haloalkoxymethyl, and haloalkenyloxymethyl with the provisothat R_(XVI-1) has a higher Cahn-lngold-Prelog stereochemical systemranking than both R_(XVI-2) and (CHR_(XVI-3))_(n)—N(A_(XVI))Q_(XVI)wherein A_(XVI) is Formula XVI-(II) and Q is Formula XVI-(III);

[0903] R_(XVI-16) is selected from the group consisting of hydrido,alkyl, acyl, aroyl, heteroaroyl, trialkylsilyl, and a spacer selectedfrom the group consisting of a covalent single bond and a linear spacermoiety having a chain length of 1 to 4 atoms linked to the point ofbonding of any aromatic substituent selected from the group consistingof R_(XVI-4), R_(XVI-8), R_(XVI-9), and R_(XVI-13) to form aheterocyclyl ring having from 5 through 10 contiguous members;

[0904] D_(XVI-1) D_(XVI-2) J_(XVI-1), J_(XVI-2) and K_(XVI-1) areindependently selected from the group consisting of C, N, O, S andcovalent bond with the provisos that no more than one of D_(XVI-1),D_(XVI-2), J_(XVI-1), J_(XVI-2) and K_(XVI-1) is a covalent bond, nomore than one D_(XVI-1), D_(XVI-2), J_(XVI-1), J_(XVI-2) and K_(XVI-1)is be O, no more than one of D_(XVI-1), D_(XVI-2), J_(XVI-1), J_(XVI-2)and K_(XVI-1) is S, one of D_(XVI-1), D_(XVI-2), J_(XVI-1), J_(XVI-2)and K_(XVI-1) must be a covalent bond when two of D_(XVI-1), D_(XVI-2),J_(XVI-1), J_(XVI-2) and K_(XVI-1) are O and S, and no more than four ofD_(XVI-1), D_(XVI-2), J_(XVI-1), J_(XVI-2) and K_(XVI-1) is N;

[0905] D_(XVI-3), D_(XVI-4), J_(XVI-3), J_(XVI-4) and K_(XVI-2) areindependently selected from the group consisting of C, N, O, S andcovalent bond with the provisos that no more than one is a covalentbond, no more than one of D_(XVI-3), D_(XVI-4), J_(XVI-3), J_(XVI-4) andK_(XVI-2) is O, no more than one of D_(XVI-3), D_(XVI-4), J_(XVI-3),J_(XVI-4) and K_(XVI-2) is S, no more than two of D_(XVI-3), D_(XVI-4),J_(XVI-3), J_(XVI-4) and K_(XVI-2) is 0 and S, one of D_(XVI-3),D_(XVI-4), J_(XVI-3), J_(XVI-4) and K_(XVI-2) must be a covalent bondwhen two of D_(XVI-3), D_(XVI-4), J_(XVI-3), J_(XVI-4) and K_(XVI-2) areO and S, and no more than four of D_(XVI-3), D_(XVI-4), J_(XVI-3),J_(XVI-4) and K_(XVI-2) are N;

[0906] R_(XVI-2) is selected from the group consisting of hydrido, aryl,aralkyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl,halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl,perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl, andcarboalkoxycyanoalkyl, with the proviso that R_(XVI-2) has a lowerCahn-Ingold-Prelog system ranking than both R_(XVI-1), and(CHR_(XVI-3))_(n)—N(A_(XVI))Q_(XVI);

[0907] R_(XVI-3) is selected from the group consisting of hydrido,hydroxy, cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl,alkoxyalkyl, heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl,haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl,dicyanoalkyl, carboxamide, and carboxamidoalkyl, with the provisos that(CHR_(XVI-3))_(n)—N(A_(XVI))Q_(XVI) has a lower Cahn-Ingold-Prelogstereochemical system ranking than R_(XVI-1) and a higherCahn-Ingold-Prelog stereochemical system ranking than R_(XVI-2);

[0908] Y_(XVI) is selected from a group consisting of a covalent singlebond, (C(R_(XVI-14))₂)_(q) wherein q is an integer selected from 1 and 2and (CH(R_(XVI-14)))_(g)—W_(XVI)—(CH(R_(XVI-14)))_(p) wherein g and pare integers independently selected from 0 and 1;

[0909] R_(XVI-14) is selected from the group consisting of hydrido,hydroxy, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl,alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl,haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;

[0910] Z_(XVI) is selected from a group consisting of a covalent singlebond, (C(R_(XVI-15))₂)_(q), wherein q is an integer selected from 1 and2, and (CH(R_(XVI-15)))_(j)—W_(XVI)—(CH(R_(XVI-15)))_(k) wherein j and kare integers independently selected from 0 and 1;

[0911] W_(XVI) is selected from the group consisting of O, C(O),C(S),C(O)N(R_(XVI-14)), C(S)N(R_(XVI-14)),(R_(XVI-14))NC(O),(R_(XVI-14))NC(S), S, S(O), S(O)₂, S(O)₂N(R_(XVI-14)),(R_(XVI-14))NS(O)₂, and N(R_(XVI-14)) with the proviso that R_(XVI-14)is other than cyano;

[0912] R_(XVI-15) is selected, from the group consisting of hydrido,cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl,haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl,haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;

[0913] R_(XVI-4), R_(XVI-5), R_(XVI-6), R_(XVI-7), R_(XVI-8), R_(XVI-9),R_(XVI-10), R_(XVI-11), R_(XVI-12), and R_(XVI-13) are independentlyselected from the group consisting of hydrido, carboxy,heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl,acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl,aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl,aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl,halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl,cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl,heteroarylamino, N-heteroarylamino-N-alkylamino, heteroaralkyl,heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl,haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy,cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl,cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl,halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio,nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino,aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl,alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl,heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl,alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl,alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl, dialkyl, amidosulfonyl, monoarylamidosulfonyl,arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl,arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl,heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl,alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl,haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky,alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl,cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo,haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl,hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl,heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturatedheterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl,carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl,carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy,phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl with the proviso that R_(XVI-4), R_(XVI-5),R_(XVI-6), R_(XVI-7), R_(XVI-8), R_(XVI-9), R_(XVI-10), R_(XVI-11),R_(XVI-)12 and R_(XVI-13) are each independently selected to maintainthe tetravalent nature of carbon, trivalent nature of nitrogen, thedivalent nature of sulfur, and the divalent nature of oxygen;

[0914] R_(XVI-4) and R_(XVI-5), R_(XVI-5) and R_(XVI-6), R_(XVI-6) andR_(XVI-7), R_(XVI-7) and R_(XVI-8), R_(XVI-9) and R_(XVI-10), R_(XVI-10)and R_(XVI-11), R_(XVI-11) and R_(XVI-12), and R_(XVI-12) and R_(XIV-13)are independently selected to form spacer pairs wherein a spacer pair istaken together to form a linear moiety having from 3 through 6contiguous atoms connecting the points of bonding of said spacer pairmembers to form a ring selected from the group consisting of acycloalkenyl ring having 5 through 8 contiguous members, a partiallysaturated heterocyclyl ring having 5 through 8 contiguous members, aheteroaryl ring having 5 through 6 contiguous members, and an aryl withthe provisos that no more than one of the group consisting of spacerpairs R_(XVI-4) and R_(XVI-5), R_(XVI-5) and R_(XVI-6), R_(XVI-6) andR_(XVI-7), and R_(XVI-7) and R_(XVI-8) is used at the same time and thatno more than one of the group consisting of spacer pairs R_(XIV-9) andR_(XVI-10), R_(XVI-10) and R_(XVI-) ₁₁, R_(XVI-11) and R_(XVI-12), andR_(XVI-12) and R_(XVI-13) can be used at the same time;

[0915] R_(XVI-4) and R_(XVI-9), R_(XVI-4) and R_(XVI-13), R_(XVI-8) andR_(XVI-9), and R_(XVI-8) and R_(XVI-13) is independently selected toform a spacer pair wherein said spacer pair is taken together to form alinear moiety wherein said linear moiety forms a ring selected from thegroup consisting of a partially saturated heterocyclyl ring having from5 through 8 contiguous members and a heteroaryl ring having from 5through 6 contiguous members with the proviso that no more than one ofthe group consisting of spacer pairs R_(XVI-4) and R_(XVI-9), R_(XVI-4)and R_(XVI-13), R_(XVI-8) and R_(XVI-9), and R_(XVI-8) and R_(XVI-13) isused at the same time.

[0916] Compounds of Formula XVI and their methods of manufacture aredisclosed in PCT Publication No. WO 00/18724, which is incorporatedherein by reference in its entirety for all purposes.

[0917] In a preferred embodiment, the CETP inhibitor is selected fromthe following compounds of Formula XVI:

[0918](2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0919](2R)-3-[[3-(3-isopropylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0920] (2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0921](2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0922](2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0923](2R)-3-[[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0924](2R)-3-[[3-(4-methylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0925](2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl-]amino]-1,1,1-trifluoro-2-propanol;

[0926](2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methly-]amino]-1,1,1-trifluoro-2-propanol;

[0927](2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0928](2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0929](2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0930](2R)-3-[[3-(3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0931](2R)-3-[[3-(3-t-butylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol:

[0932](2R)-3-[[3-(3-methylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0933](2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0934](2R)-3-[[3-(phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0935](2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0936](2R)-3-[[[3-(1,1,2,2,-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethoxy)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0937](2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoro-methyl)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0938](2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0939](2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0940](2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0941](2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0942](2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0943](2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0944](2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0945](2R)-3-[[[3-(3-trifuoromethylthio)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0946](2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0947](2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0948](2R)-3-[[3-(3-isopropylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0949](2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0950](2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0951](2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0952](2R)-3-[[3-(4-fluorophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0953](2R)-3-[[3-(4-methylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0954](2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0955](2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0956](2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(pentafluoroethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0957](2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0958] (2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0959] (2R)-3-[[3-(3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0960] (2R)-3-[[3-(3-t-butylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0961] (2R)-3-[[3-(3-methylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0962](2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0963] (2R)-3-[[3-(phenoxy)phenyl][[3(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0964](2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0965](2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0966](2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethyl)-phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0967](2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0968](2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0969](2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3,5-difluorophenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0970](2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[cyclohexylmethoxy]phenyl]-amino]-1,1,1-trifluoro-2-propanol;

[0971](2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0972](2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0973](2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0974](2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0975](2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(pentafluoroethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0976](2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0977](2R)-3-[[3-(3-isopropylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0978](2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0979] (2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0980] (2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0981] (2R)-3-[[3-(4-fluorophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0982] (2R)-3-[[3-(4-methylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1,-trifluoro-2-propanol;

[0983](2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0984](2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0985](2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(heptafluoropropyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0986](2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0987] (2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0988] (2R)-3-[[3-(3-ethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0989] (2R)-3-[[3-(3-t-butylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0990] (2R)-3-[[3-(3-methylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0991](2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0992] (2R)-3-[[3-(phenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0993](2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0994](2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0995](2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0996](2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3,5-dimethylphenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0997](2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0998](2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3,5-difluorophenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0999](2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[cyclohexylmethoxy]phenyl]-amino]-1,1,1-trifluoro-2-propanol;

[1000](2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1001](2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1002](2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1003](2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1004](2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(heptafluoropropyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1005](2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1006](2R)-3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1007](2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1008](2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1009](2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1010](2R)-3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-3-propanol;

[1011](2R)-3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1012](2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1013](2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1014](2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[2-fluoro-5-(trifluoro-methyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1015](2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1016](2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1017](2R)-3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[1018](2R)-3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[1019](2R)-3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[1020](2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1021] (2R)-3-[[3-(phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1022] (2R)-3-[[3-[3-(N,N-dimethylamino,phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1023](2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-3-propanol;

[1024](2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethyl)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1025](2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1026](2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1027](2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1028](2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[cyclohexylmethoxyl-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1029](2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1030](2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1031](2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1032](2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1033](2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-5-(trifluoro-methyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1034](2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1035](2R)-3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]I-1,1,1-trifluoro-2-propanol;

[1036](2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[2-flouro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1037](2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1038](2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1039](2R)-3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1040](2R)-3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1041](2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1042](2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1043](2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1044](2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1045](2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]aminoI-1,1,1-trifluoro-2-propanol;

[1046](2R)-3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[1047](2R)-3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[1048](2R)-3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[1049](2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1050] (2R)-3-[[3-(phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1051](2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1052](2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1053](3R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1054](2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1055](2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1056](2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1057](2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1058](2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1059](2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1060](2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1061](2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;and

[1062](2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol.

[1063] Another class of CETP inhibitors that finds utility with thepresent invention consists of quinolines of Formula XVII

[1064] and pharmaceutically acceptable forms thereof, wherein:

[1065] A_(XVII) denotes an aryl containing 6 to 10 carbon atoms, whichis optionally substituted with up to five identical or differentsubstituents in the form of a halogen, nitro, hydroxyl, trifluoromethyl,trifluoromethoxy or a straight-chain or branched alkyl, acyl,hydroxyalkyl or alkoxy containing up to 7 carbon atoms each, or in theform of a group according to the formula —NR_(XVII-4)R_(XVII-5), wherein

[1066] R_(XVII-4) and R_(XVII-5) are identical or different and denote ahydrogen, phenyl or a straight-chain or branched alkyl containing up to6 carbon atoms,

[1067] D_(XVII) denotes an aryl containing 6 to 10 carbon atoms, whichis optionally substituted with a phenyl, nitro, halogen, trifluoromethylor trifluoromethoxy, or a radical according to the formula

[1068] wherein

[1069] R_(XVII-6), R_(XVII-7), R_(XVII-) ₁₀ denote, independently fromone another, a cycloalkyl containing 3 to 6 carbon atoms, or an arylcontaining 6 to 10 carbon atom or a 5- to 7-membered, optionallybenzo-condensed, saturated or unsaturated, mono-, bi- or tricyclicheterocycle containing up to 4 heteroatoms from the series of S, Nand/or O, wherein the rings are optionally substituted, in the case ofthe nitrogen-containing rings also via the N function, with up to fiveidentical or different substituents in the form of a halogen,trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, astraight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxyor alkoxycarbonyl containing up to 6 carbon atoms each, an aryl ortrifluoromethyl-substituted aryl containing 6 to 10 carbon atoms each,or an optionally benzo-condensed, aromatic 5- to 7-membered heterocyclecontaining up to 3 heteoatoms from the series of S, N and/or O, and/orin the form of a group according to the formula —OR_(XVII-11),—SR_(XVII-12), —SO₂R_(XVII-13), or —NR_(XVII-14)R_(XVII-15);

[1070] R_(XVII-11), R_(XVII-12), and R_(XVII-13) denote, independentlyfrom one another, an aryl containing 6 to 10 carbon atoms, which is inturn substituted with up to two identical or different substituents inthe form of a phenyl, halogen or a straight-chain or branched alkylcontaining up to 6 carbon atoms,

[1071] R_(XVII-14) and R_(XVII-15) are identical or different and havethe meaning of R_(XVIl-4) and R_(XVIl-5) given above, or

[1072] R_(XVII-6) and/or R_(XVII-7) denote a radical according to theformula

[1073] R_(XVII-8) denotes a hydrogen or halogen, and

[1074] R_(XVII-9) denotes a hydrogen, halogen, azido, trifluoromethyl,hydroxyl, trifluoromethoxy, a straight-chain or branched alkoxy or alkylcontaining up to 6 carbon atoms each, or a radical according to theformula NR_(XVII-16)R_(XVII-17),

[1075] R_(XVII-16) and R_(XVII-17) are identical or different and havethe meaning of R_(XVII-4) and R_(XVII-5) above; or

[1076] R_(XVII-8) and R_(XVII-9) together form a radical according tothe formula ═O or ═NR_(XVII-18);

[1077] R_(XVII-18) denotes a hydrogen or a straight-chain or branchedalkyl, alkoxy or acyl containing up to 6 carbon atoms each;

[1078] L_(XVII) denotes a straight-chain or branched alkylene oralkenylene chain containing up to 8 carbon atoms each, which areoptionally substituted with up to two hydroxyl groups;

[1079] T_(XVII) and X_(XVII) are identical or different and denote astraight-chain or branched alkylene chain containing up to 8 carbonatoms; or

[1080] T_(XVII) and X_(XVII) denotes a bond;

[1081] V_(XVII) denotes an oxygen or sulfur atom or —NR_(XVII-19);

[1082] R_(XVII-19) denotes a hydrogen or a straight-chain or branchedalkyl containing up to 6 carbon atoms or a phenyl;

[1083] E_(XVII) denotes a cycloalkyl containing 3 to 8 carbon atoms, ora straight-chain or branched alkyl containing up to 8 carbon atoms,which is optionally substituted with a cycloalkyl containing 3 to 8carbon atoms or a hydroxyl, or a phenyl, which is optionally substitutedwith a halogen or trifluoromethyl;

[1084] R_(XVII-1) and R_(XVII-2) are identical or different and denote acycloalkyl containing 3 to 8 carbon atoms, hydrogen, nitro, halogen,trifluoromethyl, trifluoromethoxy, carboxy, hydroxy, cyano, astraight-chain or branched acyl, alkoxycarbonyl or alkoxy with up to 6carbon atoms, or NR_(XVII-20)R_(XVII-21);

[1085] R_(XVI-20) and R_(XVII-21) are identical or different and denotehydrogen, phenyl, or a straight-chain or branched alkyl with up to 6carbon atoms; and or

[1086] R_(XVII-1) and/or R_(XVII-2) are straight-chain or branched alkylwith up to 6 carbon atoms, optionally substituted with halogen,trifluoromethoxy, hydroxy, or a straight-chain or branched alkoxy withup to 4 carbon atoms, aryl containing 6-10 carbon atoms optionallysubstituted with up to five of the same or different substituentsselected from halogen, cyano, hydroxy, trifluoromethyl,trifluoromethoxy, nitro, straight-chain or branched alkyl, acyl,hydroxyalkyl, alkoxy with up to 7 carbon atoms andNR_(XVII-22)R_(XVII-23);

[1087] R_(XVII-22) and R_(XVII-23) are identical or different and denotehydrogen, phenyl or a straight-chain or branched akyl up to 6 carbonatoms; and/or

[1088] R_(XVII-1) and R_(XVII-2) taken together form a straight-chain orbranched alkene or alkane with up to 6 carbon atoms optionallysubstituted with halogen, trifluoromethyl, hydroxy or straight-chain orbranched alkoxy with up to 5 carbon atoms;

[1089] R_(XVII-3) denotes hydrogen, a straight-chain or branched acylwith up to 20 carbon atoms, a benzoyl optionally substituted withhalogen, trifluoromethyl, nitro or trifluoromethoxy, a straight-chainedor branched fluoroacyl with up to 8 carbon atoms and 7 fluoro atoms, acycloalkyl with 3 to 7 carbon atoms, a straight chained or branchedalkyl with up to 8 carbon atoms optionally substituted with hydroxyl, astraight-chained or branched alkoxy with up to 6 carbon atoms optionallysubstituted with phenyl which may in turn be substituted with halogen,nitro, trifluoromethyl, trifluoromethoxy, or phenyl or a tetrazolsubstitued phenyl, and/or an alkyl that is optionally substituted with agroup according to the formula —OR_(XVII-24);

[1090] R_(XVII-24) is a straight-chained or branched acyl with up to 4carbon atoms or benzyl.

[1091] Compounds of Formula XVII and their methods of manufacture aredisclosed in PCT Publication No. WO 98/39299, which is incorporatedherein by reference in its entirety for all purposes.

[1092] Another class of CETP inhibitors that finds utility with thepresent invention consists of 4-Phenyltetrahydroquinolines of FormulaXVIII

[1093] ,N oxides thereof, and pharmaceutically acceptable forms thereof,wherein:

[1094] A_(XVIII) denotes a phenyl optionally substituted with up to twoidentical or different substituents in the form of halogen,trifluoromethyl or a straight-chain or branched alkyl or alkoxycontaining up to three carbon atoms;

[1095] D_(XVIII) denotes the formula

[1096] R_(XVIII-5) and R_(XVIII-6) are taken together to form ═O; or

[1097] R_(XVIII-5) denotes hydrogen and R_(XVIII-6) denotes halogen orhydrogen; or

[1098] R_(XVIII-5) and R_(XVIII-6) denote hydrogen;

[1099] R_(XVIII-7) and R_(XVIII-8) are identical or different and denotephenyl, naphthyl, benzothiazolyl, quinolinyl, pyrimidyl or pyridyl withup to four identical or different substituents in the form of halogen,trifluoromethyl, nitro, cyano, trifluoromethoxy, —SO₂—CH₃ orNR_(XVIII-9)R_(XVIII-10);

[1100] R_(XVIII-9) and R_(XVIII-10) are identical or different anddenote hydrogen or a straight-chained or branched alkyl of up to threecarbon atoms;

[1101] E_(XVIII) denotes a cycloalkyl of from three to six carbon atomsor a straight-chained or branched alkyl of up to eight carbon atoms;

[1102] R_(XVIII-1) denotes hydroxy;

[1103] R_(XVIII-2) denotes hydrogen or methyl;

[1104] R_(XVIII-3) and R_(XVIII-4) are identical or different and denotestraight-chained or branched alkyl of up to three carbon atoms; or

[1105] R_(XVIII-3) and R_(XVIII-4) taken together form an alkenylenemade up of between two and four carbon atoms.

[1106] Compounds of Formula XVIII and their methods of manufacture aredisclosed in PCT Publication No. WO 99/15504 and U.S. Pat. No. 56,291,477, both of which are incorporated herein by reference in theirentireties for all purposes.

[1107] The invention is particularly advantageous for the class of drugswhich are both acid-sensitive and low-solubility. Exemplaryacid-sensitive, low-solubility drugs include(+)-N-{3-[3-(4-fluorophenoxy)phenyl]-2-cyclopenten-1-yl}-N-hydroxyurea;omeprazole; etoposide; famotidine; erythromycin; quinapril;lansoprazole; progabide; as well as CCR1 inhibitors such asquinoxaline-2-carboxylic acid[4(R)-carbamoyl-1(S)-3-fluorobenzyl-2(S),7-dihydroxy-7-methyl-octyl]amideand quinoxaline-2-carboxylic acid[1-benzyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide.

[1108] The invention is useful for improving the intrinsic dissolutionrate of compounds selected from the following. The intrinsic dissolutionrate is defined as the rate of dissolution of a pure pharmaceuticalactive ingredient when conditions such as surface area,agitation-stirring speed, pH and ionic-strength of the dissolutionmedium are kept constant. Intrinsic dissolution rate is further definedas being measured in water at 37° C. using a USP II dissolutionapparatus equipped with a Wood's apparatus (Wood, J H; Syarto, J E andLetterman, H: J.Pharm. Sci. 54 (1965), 1068) with a stirring speed of 50rpm. The intrinsic dissolution rate is defined in terms of mg of drugdissolved per minute from a unit surface area, therefore, the intrinsicdissolution rate is referred to in units of mg/min.cm².

[1109] The compositions and methods of the invention are particularlyuseful for compounds with an intrinsic dissolution rate of preferablyless than 0.1 mg/min.cm² and more preferably with less than 0.05mg/min.cm².

[1110] Turning now to the chemical structures of specific CCR1inhibitors, one class of CCR1 inhibitors that finds utility with thepresent invention consists of dihydroxyhexanoic acid derivatives havingthe Formula CCR1-I

[1111] wherein R₁ is (C₂-C₉) heteroaryl optionally substituted with one,two or three substituents independently selected from the groupconsisting of hydrogen, halo, cyano, (C₁-C₆)alkyl optionally substitutedwith one, two or three fluorine atoms, hydroxy, hydroxy-(C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

[1112] wherein R₂ is phenyl-(CH₂)_(m)—, naphthyl-(CH₂)_(m)—,(C₃-C₁₀)cycloalkyl-(CH₂)_(m)—, (C₁-C₆)alkyl or(C₂-C₉)heteroaryl-(CH₂)_(m)—, wherein each of said phenyl, naphthyl,(C₃-C₁₀)cycloalkyl or (C₂-C₉)heteroaryl moieties of saidphenyl-(CH₂)_(m)—, naphthyl-(CH₂)_(m)—, (C₃-C₁₀)cycloalkyl-(CH₂)_(m)— or(C₂-C₉)heteroaryl-(CH₂)_(m)— groups may optionally be substituted withone, two, or three substituents independently selected from the groupconsisting of hydrogen, halo, cyano, (C₁-C₆)alkyl, hydroxy,hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,phenoxy, benzyloxy, (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and(C₂-C₉)heteroaryl;

[1113] wherein R³ is hydrogen, (C₁-C₁₀)alkyl,(C₃-C₁₀)cycloalkyl-(CH₂)_(n)—, (C₂-C₉)heterocycloalkyl-(CH₂)_(n)—,(C₂-C₉)heteroaryl-(CH₂)_(n)— or aryl-(CH₂)_(n)—; wherein n is aninterger from zero to six;

[1114] wherein said R₃ (C₁-C₁₀)alkyl group may optionally be substitutedwith one or more substituents, (preferably from one to threesubstituents) independently selected from hydrogen, halo, CN,(C₁-C₆)alkyl, hydroxy, hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl; andwherein any of the carbon-carbon single bonds of said (C₁-C₁₀)alkyl mayoptionally be replaced by a carbon-carbon double bond;

[1115] wherein the (C₃-C₁₀)cycloalkyl moiety of said R₃(C₃-C₁₀)cycloalkyl-(CH₂)_(n)— group may optionally be substituted by oneto three substitutents independently selected from the group consistingof hydrogen, halo, CN, (C₁-C₆)alkyl, hydroxy, hydroxy-(C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkyl HN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

[1116] wherein the (C₂-C₉)heterocycloalkyl moiety of said R₃(C₂-C₉)heterocycloalkyl-(CH₂)_(n)— group may contain from one to threeheteroatoms independently selected from nitrogen, sulfur,oxygen, >S(═O), >SO₂ or >NR⁶, wherein said (C₂-C₉)heterocycloalkylmoiety of said (C₂-C₉)heterocycloalkyl-(CH₂)_(n)— group may optionallybe substituted on any of the ring carbon atoms capable of forming anadditional bond (preferably one to three substitutents per ring) with asubstituent independently selected from the group consisting ofhydrogen, halo, CN, (C₁-C₆)alkyl, hydroxy, hydroxy-(C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

[1117] wherein the (C₂-C₉)heteroaryl moiety of said R³(C₂-C₉)heteroaryl-(CH₂)_(n)— group may contain from one to threeheteroatoms independently selected from nitrogen, sulfur or oxygen,wherein said (C₂-C₉)heteroaryl moiety of said(C₂-C₉)heteroaryl-(CH₂)_(n)— group may optionally be substituted on anyof the ring carbon atoms capable of forming an additional bond(preferably one to three substitutents per ring) with a substituentselected from the group consisting of hydrogen, halo, CN, (C₁-C₆)alkyl,hydroxy, hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl; and

[1118] wherein said aryl moiety of said R₃ aryl-(CH₂)_(n)— group isoptionally substituted phenyl or naphthyl, wherein said phenyl andnaphthyl may optionally be substituted with from one to threesubstituents independently selected from the group consisting ofhydrogen, halo, CN, (C₁-C₆)alkyl, hydroxy, hydroxy-(C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkyl HN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

[1119] or R₃ and the carbon to which it is attached form a five to sevenmembered carbocyclic ring, wherein any of the carbon atoms of said fivemembered carbocyclic ring may optionally be substituted with asubstituent selected from the group consisting of hydrogen, halo, CN,(C₁-C₆)alkyl, hydroxy, hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl, (C_(1-C)₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl, H₂N—(C═O)—,(C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—, H₂N(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl,H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH, (C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;wherein one of the carbon-carbon bonds of said five to seven memberedcarbocyclic ring may optionally be fused to an optionally substitutedphenyl ring, wherein said substitutents may be independently selectedfrom hydrogen, halo, CN, (C₁-C₆)alkyl, hydroxy, hydroxy-(C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C_(1-C) ₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl- SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

[1120] wherein R₄ is hydrogen, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C═O)—, (C₃-C₁₀)cycloalkyl-(CH₂)_(q)—,(C₂-C₉)heterocycloalkyl-(CH₂)_(q)—, (C₂-C₉)heteroaryl-(CH₂)_(q)—,phenyl-(CH₂)_(q)—, or naphthyl-(CH₂)_(q)—; wherein said(C₂-C₉)heterocycloalkyl, (C₂-C₉)heteroaryl, phenyl and naphthyl groupsmay be optionally substituted with one or two substituents from thegroup consisting of hydrogen, halo, cyano, (C₁-C₆)alkyl, hydroxy,hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl, (C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino (C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

[1121] wherein R₅ is hydrogen, (C₁-C₆)alkyl or amino; or

[1122] R₄ and R₅ together with the nitrogen atom to which they areattached form a (C₂-C₉)heterocycloalkyl group optionally substitutedwith one or two substituents selected from the group consisting ofhydrogen, halo, cyano, (C₁-C₆)alkyl, hydroxy, hydroxy-(C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl, (C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂ amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino (C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

[1123] wherein R⁶ is hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy-(CH₂)_(g)—,(C₁-C₆)alkoxy(C═O)—(CH₂)_(g)—, (C₁-C₆)alkyl-(SO₂)—(CH₂)_(g)—,(C₆-C₁₀)aryloxy-(CH₂)_(g)—, (C₆-C₁₀)aryloxy(C═O)—(CH₂)_(g)—, or(C₆-C₁₀)aryl-(SO₂)—(CH₂)_(g)—;

[1124] wherein g is an integer from zero to four;

[1125] wherein m is an integer from zero to four;

[1126] wherein n is an interger from zero to six;

[1127] with the proviso that when one of R⁴ or R⁵ is hydrogen, and theother of R⁴ or R⁵ is (C₁-C₆)alkyl; R² is (C₃-C₁₀)cycloalkyl or isopropyland R³ is (C₃-C₅)alkyl, phenyl, methylvinyl, dimethylvinyl, halovinyl,hydroxy(C₁-C₃)alkyl or amino(C₁-C₄)alkyl then R¹ must be other thanindol-5-yl, 6-azaindol-2-yl, 2,3-dichloro-pyrrol-5-yl,4-hydroxyquinolin-3-yl, 2-hydroxyquinoxalin-3-yl, 6-azaindolin-3-yl, oroptionally substituted indol-2 or 3-yl;

[1128] and the pharmaceutically acceptable salts of such compounds.

[1129] Unless otherwise indicated, the alkyl and alkenyl groups referredto herein, as well as the alkyl moieties of other groups referred toherein (e.g., alkoxy), may be linear or branched, and they may also becyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl) or be linear or branched and contain cyclic moieties. Suchalkyl and alkoxy groups may be substituted with one, two or threehalogen and/or hydroxy atoms, preferably fluorine atoms.

[1130] Unless otherwise indicated, “halogen” includes fluorine,chlorine, bromine, and iodine.

[1131] “(C₃-C₁₀)cycloalkyl” when used herein refers to cycloalkyl groupscontaining zero to two levels of unsaturation such as cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,1,3-cyclohexadiene, cycloheptyl, cycloheptenyl, bicyclo[3.2.1]octane,norbornanyl, and the like.

[1132] “(C₂-C₉)heterocycloalkyl” when used herein refers topyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl,pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl,isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl,1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl,piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl,1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl,tetrahydroazepinyl, piperazinyl, chromanyl, and the like. One ofordinary skill in the art will understand that the connection of said(C₂-C₉)heterocycloalkyl rings is through a carbon or a sp³ hybridizednitrogen heteroatom.

[1133] “(C₂-C₉)heteroaryl” when used herein refers to furyl, thienyl,thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl,triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl,pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl,6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl, 5, 6, 7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl,benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl,isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl,indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl,quinoxalinyl, quinazolinyl, benzoxazinyl, and the like. One of ordinaryskill in the art will understand that the connection of said(C₂-C₉)heterocycloalkyl rings is through a carbon atom or a sp³hybridized nitrogen heteroatom.

[1134] “Aryl” when used herein refers to phenyl or naphthyl.

[1135] “Protected amine” and “protected amino” refers to an amine groupwith one of the hydrogen atoms replaced with a protecting group (P). Anysuitable protecting group may be used for amine protection. Suitableprotecting groups include carbobenzyloxy, t-butoxy carbonyl (BOC) or9-fluorenyl-methylenoxy carbonyl.

[1136] Compounds of Formula CCR1-I and their methods of manufacture aredisclosed in commonly assigned U.S. patent application Ser. No.09/380,269, filed Feb. 5, 1998, U.S. patent application Ser. No.09/403,218, filed Jan. 18, 1999, PCT Publication No. WO98/38167, and PCTPublication No. WO99/40061, all of which are incorporated herein byreference in their entireties for all purposes.

[1137] In a preferred embodiment, the CCR1 inhibitor is selected fromone of the following compounds of Formula CCR1-I:

[1138] q uinoxaline-2-carboxylic acid 4(R)-carbamoyl-1(S)-(3-chloro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;

[1139] 7,8-difluoro-quinoline-3-carboxylic acid(1S)-benzyl-4(R)-carbamoyl-2(S),7-dihydroxy-7-methyl-octyl)-amide;

[1140] 6,7,8-trifluoro-quinoline-3-carboxylic acid(1(S)-benzyl-4(R)-carbamoyl-2(S),7-dihydroxy-7-methyl-octyl)-amide;

[1141] quinoxaline-2-carboxylic acid[4(R)-carbamoyl-1(S)-(3-fluoro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;

[1142] quinoxaline-2-carboxylic acid(1(S)-benzyl-2(S),7-dihydroxy-4(R)-hydroxycarbamoyl-7-methyl-octyl)-amide;

[1143] quinoxaline-2-carboxylic acid[4(R)-carbamoyl-1(S)-(2-chloro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;

[1144] quinoxaline-2-carboxylic acid[1(S)-(2-fluoro-benzyl)-2(S),7-dihydroxy-4(R)-hydroxycarbamoyl-7-methyl-octyl]-amide;

[1145] quinoxaline-2-carboxylic acid[4(R)-carbamoyl-1(S)-(2-fluoro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;

[1146] quinoxaline-2-carboxylic acid[1(S)-(3,4-difluoro-benzyl)-2(S),7-dihydroxy-4(R)-hydroxycarbamoyl-7-methyl-octyl]-amide;

[1147] quinoxaline-2-carboxylic acid[4(R)-carbamoyl-1(S)-(3,4-difluoro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;

[1148] quinoxaline-2-carboxylic acid(4(R)-carbamoyl-2(S),7-dihydroxy-7-methyl-1(S)-naphthalen-1-ylmethyl-octyl)-amide;

[1149] 7,8-difluoro-quinoline-3-carboxylic acid1(S)-benzyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide;

[1150] 8-fluoro-quinoline-3-carboxylic acid1(S)-benzyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide;

[1151] quinoxaline-2-carboxylic acid[4(R)-carbamoyl-7-fluoro-1-(3(S)-fluoro-benzyl)-2(S)-hydroxy-7-methyl-octyl]-amide;

[1152] quinoxaline-2-carboxylic acid[4(R)-carbamoyl-1-(2(S)-fluoro-benzyl)-2(S)-hydroxy-7-methyl-octyl]-amide;

[1153] quinoxaline-2-carboxylic acid[1(S)-benzyl-4(S)-carbamoyl-4(S)-(2,6-dimethyl-tetrahydro-pyran-4-yl)-2(S)-hydroxy-butyl]-amide;

[1154] quinoxaline-2-carboxylic acid1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide;

[1155] quinoxaline-2-carboxylic acid1(S)-benzyl-5-cyclohexyl-2(S)-hydroxy-4(R)-methylcarbamoyl-pentyl)-amide;

[1156] quinoxaline-2-carboxylic acid1(S)-cyclohexylmethyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide;

[1157] quinoxaline-2-carboxylic acid[1(S)-benzyl-2(S)-hydroxy-4(S)-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-butyl]-amide;

[1158] quinoxaline-2-carboxylic acid [1(S)-benzyl-4(S)-(4,4-difluoro-1-hydroxy-cyclohexyl)-2(S)-hydroxy-4-hydroxycarbamoyl-butyl]-amide;

[1159] quinoxaline-2-carboxylic acid[1(S)-benzyl-4(S)-carbamoyl-4(S)-(4,4-difluoro-cyclohexyl)-2(S)-hydroxy-butyl]-amide;

[1160] quinoline-3-carboxylic acid(1(S)-benzyl-4(S)-carbamoyl-4-cyclohexyl-2(S)-hydroxy-butyl)-amide;

[1161] quinoxaline-2-carboxylic acid(4(R)-carbamoyl-2(S)-hydroxy-7-methyl-1(S)-thiophen-2-ylmethyl-octyl)-amide;

[1162] quinoxaline-2-carboxylic acid1(S)-benzyl-4(R)-carbamoyl-7-chloro-2(S)-hydroxy-oct-6-enyl)-amide;

[1163] quinoxaline-2-carboxylic acid1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-5-phenyl-pentyl)-amide;

[1164]N-1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-5,6-dichloro-nicotinamide;

[1165] quinoxaline-2-carboxylic acid(4(R)-carbamoyl-2(S)-hydroxy-7-methyl-1(S)-thiazol-4(R)-ylmethyl-octyl)-amide;

[1166] benzothiazole-2-carboxylic acid1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide;and

[1167] benzofuran-2-carboxylic acid1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide.

[1168] In another preferred embodiment, the CCR1 compound has a formulaIa-1:

[1169] wherein the substituents are as defined above.

[1170] In a preferred method of making the compound Ia-1, the reactionis started with Scheme 1. In the herein described processes, thesubstituents are as defined for CCR1-I, and the following:

[1171] R₇ is hydroxy, (C₁-C₆)alkyl, or phenyl wherein the phenyl groupunsubstituted or substituted with one, two, or three (C₁-C₆)alkyl,hydroxy, or halogen groups;

[1172] R₈ is hydroxy or halogen;

[1173] R₉ is phenyl, naphthyl, (C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl or(C₂-C₉)heteroaryl, wherein each of said phenyl, naphthyl,(C₃-C₁₀)cycloalkyl or (C₂-C₉)heteroaryl groups may be unsubstituted orsubstituted with one, two, or three substituents independently selectedfrom the group consisting of halogen, cyano, and (C₁-C₆)alkyl;

[1174] P is a protecting group;

[1175] X is hydroxy or halogen; and

[1176] q is 0, 1, 2, 3, or 4.

[1177] In scheme 1 step 1, a compound of the formula (VI-1) is reducedwith a reducing agent under heat to form a compound of the formula(VId-1). In one embodiment, the reducing agent is aluminumtriisopropoxide and isopropanol. Preferably, the temperature ismaintained above room temperature, more preferably between about 60° C.and about 82° C. The product alcohol can be isolated by either coolingthe reaction mixture to room temperature, diluting with more isopropanoland collecting the crystalline material or by cooling the reaction toroom temperature and adding 1N HCL and water and collecting thecrystalline material.

[1178] Step 2 of scheme 1 includes reacting a compound of the formulaR₇-SO₂—X and a compound of the formula (VId-1) in the presence of a baseto form the compound of the formula (VIe-1). Any amine base is suitable,including pyridine, triethylamine, N-methylmayholine, anddiisoyropylethylamine. In one embodiment, R₇—SO2-R₈ is p-toluenesulfonicacid, methanesulfonic acid, sulfuric acid, or methanesulfonyl chloride.In another embodiment, the conversion of hydroxy dioxane (VId-1) todioxane oxazolidinone (VIe-1) can be achieved by treatment of thehydroxy dioxane (VId-1) with methanesulfonyl chloride and triethylaminein tetrahydrofuran solution and heating the mixture to cause thecyclization of the mesylate formed in situ to the oxazolidinone.

[1179] In step 3 of scheme 1, a compound of the formula (VIf-1) may beformed by heating the compound of the formula (VIe-1). The reaction mayproceed by dissolving compound VIe-1 in a solvent such as pyridine orN-methyl imidazole and heating the mixture for several hours attemperature from about 50° C. to about 100° C.; preferably at about 80°C. The mesylate (VIf-1 ) may be recovered by extraction into an organicsolvent such as ethyl acetate and removal of the amine solvents byextraction of the solution with aqueous acid.

[1180] Step 4 of scheme 1 depicts reacting hydroxylamine hydrochloride,a compound of the formula R₇—SO₂—X, and a compound of the formula(VIf-1) to form a compound of the formula (VIg-1). In one embodiment,R₇—SO2-X is p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid,or methanesulfonyl chloride. The reaction may occur in a solvent, suchas methanol. In one embodiment, the reaction occurs in methanol withtosic acid at reflux for 8 to 24 hours. The resulting nitrileoxazolidinone contains a small amount of the corresponding ethyl esterwhich is not removed since it also is converted to the desired lactonein subsequent steps.

[1181] Step 5 of scheme 1 includes a) hydrolyzing a compound of theformula (VIg-1) with an aqueous solution in the presence of a base, b)protecting the amine group of the compound so formed, and c) cyclizingthe compound so formed with heat and an acid catalyst. In oneembodiment, the compound VIg-1 is hydrolyzed with sodium hydroxide. ThepH is adjusted to approximately 10 and tetrahydrofuran and BOCdicarbonate are added. This provides the protected hydroxy acid, whichmay be heated in 10% acetic acid and toluene to provide the protectedamine lactone (V-1).

[1182] The compound of formula (V-1) may also be produced according toscheme 2.

[1183] In step 1 of scheme 2, a compound of the formula (VI-1) may bereacted with ozone to for a compound of the formula (VIa-1). Thecompound VI-1 may be present in a solvent, such as ethyl acetate, andthe ozone introduced through sparging at a temperature below roomtemperature, preferably at about −15° C., until the starting dioxaneketone is substantially reacted. Any excess ozone may be removed bybubbling nitrogen through the solution. The resulting crude ketone estermixture may be isolated after treatment with aqueous sodium bisulfite toremove any hydroperoxides.

[1184] Alternatively, in step 1 of scheme 2, the compound of the formula(VIa-1) may be formed by reacting hypochlorous acid and a compound ofthe formula (VI-1). Such an oxidation reaction typically produceschlorinated forms of the compound VIa-1 as side products in addition othe compound VIa-1. This oxidation reaction proceeds by mixing thecompound VI-1 in solvent, such as acetic acid and/or acetone, and addingsodium hypochlorite, while keeping the mixture at a low temperature,preferably at or below about 0° C.

[1185] As a means to convert the side product chlorinated forms of thecompound VIa-1 to compounds of the formula V-1, the compounds formedfrom the hypochlorous acid oxidation reaction may optionally behydrogenated by reaction with hydrogen in the presence of a catalyst.The hydrogenation may include introducing the products from thehypochlorous acid oxidation reaction into a solvent system oftetrahydrofuran and water, followed by addition of a Pd/C catalyst. Theresulting mixture is subjected to hydrogen above atmospheric pressureand temperature. In one embodiment, the pressure is about 80 pounds persquare inch and the temperature is maintained from about 60° C. to about70° C. until the reaction is substantially complete.

[1186] In step 2 of scheme 2, the compound of the formula (VIb-1) may beformed by reacting a silyating agent and a compound of the formula(VIa-1) and reacting the compound so formed with a reducing agent. Inone embodiment, the reducing agent is N-selectride. In anotheremodiment, the silyating agent is 1,1,1,3,3,3-hexamethyl-disilazane. Thereduction reaction may occur at temperatures below about 0° C.,preferably below about −20° C., more preferably below about −50° C. Inaddition, the reducing agent may be present in slight excess.

[1187] In step 3 of scheme 2, the compound of the formula (V-1) isformed by heating a compound of the formula (VIb-1) in the presence ofan acid catalyst, such as acetic acid. In one embodiment, thecyclization reaction occurs by introducing the compound VIb-1 into asolvent mixture, such as toluene and 10% acetic acid, at the solventreflux temperature for 8 to 16 hours. This provides the desired lactoneas a crystalline solid after work up.

[1188] One method of making the compound of the formula (VI-1) is byreacting a compound of the formula (VII-1)

[1189] with a Grinard reagent formed in situ by addition of2-(2-bromo-ethyl)-[1,3]dioxane to a mixture comprising magnesium and thecompound of the formula (VII-1). In one embodiment, the mixture furthercomprises methyl magnesium chloride and/or methyl magnesium bromide in asolvent. Any exotherm formed from the reaction may be controlled by therate of addition of the bromide.

[1190] The compound of the formula (VII-1) may be formed by couplingN,O-dimethylhydroxylamine hydrochloride and a compound of the formula(VIII-1)

[1191] This coupling reaction may be performed by mixed anhydrideprocedure. In one mixed anhydride procedure, compound VIII-1 is combinedwith methylene chloride and N-methylmorpholine is added followed byisobutyl chloroformate. In a separate mixture, a slurry ofN,O-dimethylhydroxylamine hydrochloride is treated withN-methylmorpholine. The two reaction mixtures are combined and thenquenched with a solution of citric acid in water. This procedurepreferably operates at a temperature below about 20° C., more preferablybelow about 0° C.

[1192] Compounds of formula (V-1) may be used to produce compounds ofthe formula (IVa1-1) according to scheme 3:

[1193] In step 1 of scheme 3, the compound of the formula (IVa1-1) maybe formed by reacting 4-halo-2-methyl-2-butene and a compound of theformula (V-1) in the presence of a base. Exemplary bases include lithiumdialkyl amides such as lithium N-isopropyl-N-cyclohexylamide, lithiumbis(trimethylsilyl)amide, lithium di-isopropylamide, and potassiumhydride. Suitable solvents include aprotic polar solvents such as ethers(such as tetrahydrofuran, glyme or dioxane), benzene, or toluene,preferably tetrahydrofuran. The aforesaid reaction is conducted at atemperature from about −78° C. to about 0° C., preferably at about −78°C. In one embodiment, alkylation of the lactone (V-1) is accomplished byreacting the lactone (V-1) with lithium bis(trimethylsilyl)amide anddimethylallyl bromide in tetrahydrofuran at a temperature from about−78° C. to about −50° C. Reaction times range from several hours or ifan additive such as dimethyl imidazolidinone is present, the reactionmay be complete in minutes.

[1194] Compounds of formula (IVa1-1) may be used to produce compounds ofthe formula (Ia-1) according to scheme 4:

[1195] In step 1 of scheme 4, a compound of the formula (IlIa1-1) isformed by reacting a compound of the formula (IVa1-1) with phosphoricacid. Preferably, this reaction occurs in any suitable solvent, such asnon-alcoholic solvents. Two preferred solvents include tetrahydrofuranand dichloroethane. The reaction may take place at any suitabletemperature, preferably from about −25° C. to about 120° C., morepreferably from about 15° C. to about 40° C. Reaction time is dependenton temperature and batch size, amount other factors, but typicallyreaction time is from about 2 hours to about 14 hours.

[1196] Step 2 of scheme 4 depicts coupling a compound IIIa1-1 with acompound having the formula R₁—CO—X to form a compound having theformula (IIa1-1). This coupling reaction is generally conducted at atemperature from about −30° C. to about 80° C., preferably from about 0°C. to about 25° C. The coupling reaction may occur with a couplingreagent that activates the acid functionality. Exemplary couplingreagents include dicyclohexylcarbodiimide/hydroxybenzotriazole(DCC/HBT), N-3-dimethylaminopropyl-N′-ethylcarbodiimide (EDC/HBT),2-ethyoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), carbonyldiimidazole (CDI), and diethylphosphorylcyanide. The coupling isconducted in an inert solvent, preferably an aprotic solvent, such astetrahydrofuran, acetonitirile, dichloromethane, chloroform, orN,N-dimethylformamide. One preferred solvent is tetrahydrofuran. In oneembodiment, quinoxaline acid is combined with CDI in anhydroustetrahydrofuran and heated to provide the acyl imidazole.

[1197] Compound IIIa1-1 is added to the acyl imidazole at roomtemperature to form the compound IIa1-1.

[1198] Step 3 of scheme 4 includes reacting the compound. of formulaIIa1-1 with an amine having a formula NHR₄R₅ to form a compound of theformula (Ia-1). In one embodiment, the amine is ammonia either anhydrousin an organic solvent or as an aqueous solution of ammonium hydroxideadded to a polar solvent at a temperature from about −10° C. to about35° C., preferably at about 30° C. Suitable solvents include, alcohols,such as methanol, ethanol, or butanols; ethers such as tetrahydrofuran,glyme or dioxane; or a mixture thereof, including aqueous mixtures.Preferably the solvent is methanol. In one embodiment, the compoundIIa1-1 is dissolved in methanol which has been saturated with ammoniagas. In another embodiment, the compound IIa1-1 in methanol is treatedwith ammonium hydroxide in tetrahydrofuran at room temperature.

[1199] Scheme 5 represents an alternative method to form compounds offormula Ia-1 from compounds of formula IVa1-1.

[1200] In step 1 of scheme 5, a compound of the formula (IVa1-1) isreacted with a compound of the formula R_(g)—SO₂—X to form a compound ofthe formula (IVa2-1). Any suitable acidic deprotection reaction may beperformed. In one example, an excess of p-toluenesulfonic acid hydratein ethyl acetate is introduced to the compound IVal-1 at roomtemperature. Suitable solvents include ethyl acetate, alcohols,tetrahydrofuran, and mixtures thereof. The reaction may proceed atambient or elevated temperatures. Typically, the reaction issubstantially complete within two and twelve hours. The resultingcompound IVa2-1 may be crystallized and separated from the reactionmixture, and may be further purifiedto remove impurities byrecrystallization from hot ethyl acetate.

[1201] In step 2 of scheme 5, the compound IVa2-1 may be coupled with acompound having the formula R₁—CO—X to form a compound of the formula(IIIa2-1). This coupling reaction is generally conducted at atemperature from about −30° C. to about 80° C., preferably from about 0°C. to about 25° C. The coupling reaction may occur with a couplingreagent that activates the acid functionality. Exemplary couplingreagents include dicyclohexylcarbodiimide/hydroxybenzotriazole(DCC/HBT), N-3-dimethylaminopropyl-N′-ethylcarbodiimide (EDC/HBT),2-ethyoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), carbonyldiimidazole (CDI)/dimethylaminopyridine (DMAP), anddiethylphosphorylcyanide. The coupling is conducted in an inert solvent,preferably an aprotic solvent, such as acetonitirile, dichloromethane,chloroform, or N,N-dimethylformamide. One preferred solvent is methylenechloride. In one embodiment, quinoxaline acid is combined with methylenechloride, oxalyl chloride and a catalytic amount ofN,N-dimethylformamide to form an acid chloride complex. The compoundIVa2-1 is added to the acid chloride complex followed by triethylamineat a temperature from about 0° C. to about 25° C. to form the compoundIIIa2-1.

[1202] Step 3 of scheme 5 includes reacting a compound IIa2-1 withtrifluoroacetic acid to produce a compound of the formula (IIa2-1). Inone embodiment, the hydration with trifluoroacetic acid occurs inmethylene chloride solution at room temperature. The hydration may takeseveral hours to complete at room temperature. A catalytic amount ofsulfuric acid can be added to the reaction solution to increase the rateof reaction.

[1203] Step 4 of scheme 5 includes reacting the compound of formulaIIa2-1 with an amine having a formula NHR₄R₅to form a compound of theformula (Ia-1). In one embodiment, the amine is ammonia either anhydrousin an organic solvent or as an aqueous solution of ammonium hydroxideadded to a polar solvent at a temperature from about −10° C. to about35° C., preferably at about 30° C. Suitable solvents include, alcohols,such as methanol, ethanol, or butanols; ethers such as tetrahydrofuran,glyme or dioxane; or a mixture thereof, including aqueous mixtures.Preferably the solvent is methanol. In one embodiment, the compoundIIa2-1 is dissolved in methanol which has been saturated with ammoniagas. In another embodiment, the compound IIa2-1 in methanol is treatedwith ammonium hydroxide in tetrahydrofuran at room temperature.

NEUTRAL DISPERSION POLYMERS

[1204] The neutral polymers suitable for use in the dispersions of thepresent invention are pharmaceutically acceptable and should be inert,in the sense that they do not chemically react with the drug in anadverse manner when present in the composition. The polymer should alsohave an aqueous-solubility of at least 0.1 mg/mL over at least a portionof the pH range of 1-8.

[1205] The polymer is “neutral,” meaning that the dispersion polymerpossesses substantially no acidic functional groups. By “substantiallyno acidic functional groups” is meant that the number of acidic groupscovalently attached to the polymer is less than about 0.05milliequivalents per gram of polymer. Preferably, the number is lessthan about 0.02 millequivalents per gram of polymer. By “acidic groups”is meant functional groups that, when attached to the polymer, havepK_(a) values in a humid or aqueous environment of about 5 or less.Preferably, the pK_(a) value of the functional groups on the neutralpolymer is greater than about 6. Thus, the neutral polymers may containionic groups as long as the groups are not acidic.

[1206] However, for many drugs, particularly those that are alsosensitive to basic conditions, e.g., “base-sensitive drugs,” it ispreferred that the neutral polymers be substantially nonionizable. By“substantially nonionizable” is meant that the number of “ionizablegroups” covalently attached to the polymer is less than about 0.05milliequivalents per gram of polymer and preferably less than about 0.02milliequivalents per gram of polymer. “Ionizable groups” are those thatare at least about 10% ionized over at least a portion of thephysiologically relevant pH 1 to 8 range and thus such groups havepK_(a) values of about 0 to 9.

[1207] The neutral dispersion polymer may be cellulosic ornon-cellulosic. A preferred class of neutral cellulosic dispersionpolymers are those with at least one ester- and/or ether-linkedsubstituent in which the polymer has a degree of substitution of atleast 0.05 for each substituent. It should be noted that in the polymernomenclature used herein, ether-linked substituents are recited prior to“cellulose” as the moiety attached to the ether group; for example,“methyl cellulose” has a methyl moiety ether-linked to the polymer. Incontrast, ester-linked substituents are recited after “cellulose” as thecarboxylate; for example, “cellulose acetate” has an acetate moietyester-linked to the polymer.

[1208] It should also be noted that a polymer name such as “celluloseacetate butyrate” refers to any of the family of cellulosic polymersthat have acetate and butyrate groups attached via ester linkages to asignificant fraction of the cellulosic polymer's hydroxyl groups.Generally, the degree of substitution of each substituent group canrange from about 0.05 to 2.9 as long as the other criteria of thepolymer are met. “Degree of substitution” refers to the average numberof the three hydroxyls per saccharide repeat unit on the cellulose chainthat have been substituted. For example, if all of the hydroxyls on thecellulose chain have been butyrate substituted, the butyrate degree ofsubstitution is 3. Also included within each polymer family type arecellulosic polymers that have additional substituents added inrelatively small amounts that do not substantially alter the performanceof the polymer.

[1209] Polymer substituents may be either non-ionizable or ionizable;however, the ionizable groups may not be acidic groups. Exemplaryether-linked non-ionizable substituents include: alkyl groups, such asmethyl, ethyl, propyl, butyl, etc.; hydroxy alkyl groups such ashydroxymethyl, hydroxyethyl, hydroxypropyl, etc.; and aryl groups suchas phenyl. Exemplary ester-linked non-ionizable groups include: alkylategroups, such as acetate, propionate, butyrate, etc.; and arylate groupssuch as phenylate. However, when ester-linked non-ionizable groups areincluded, the polymer may need to include a sufficient amount of ahydrophilic substituent so that the polymer has at least some watersolubility at any physiologically relevant pH of from 1 to 8. In thecase of neutral dispersion polymers, such hydrophilic substituents mayconsist of non-acidic ionizable groups such as amino-functionalizedgroups or phenolate groups. In the case of non-ionizable neutraldispersion polymers, such hydrophilic groups are non-ionizablesubstituents such as alcohol, ether or ester groups.

[1210] Exemplary neutral non-ionizable cellulosic polymers that may beused to form the dispersion include: hydroxypropyl methyl celluloseacetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl methyl cellulose, hydroxyethyl celluloseacetate, and hydroxyethyl ethyl cellulose.

[1211] Exemplary neutral, but ionizable cellulosic polymers, includeaminoethyl cellulose, aminoethyl cellulose acetate, hydroxypropyl aminoethyl cellulose and hydroxybenzyl cellulose.

[1212] Another class of neutral dispersion polymers ig;non-cellulosic,neutral polymers. Such polymers may be either non-ionizable orionizable. Exemplary non-ionizable, neutral polymers include vinylpolymers and copolymers having substituents of hydroxyl, alkylacyloxy,and cyclicamido. Exemplary non-cellulosic, neutral polymers includehydroxyethyl methacrylate, polyvinylhydroxyethyl ether, polyethyleneglycol, and polyoxyethylene-polyoxypropylene block copolymers also knownas poloxamers.

[1213] Exemplary ionizable neutral polymers include amine-functionalizedpolyacrylates and polymethacrylates, some of which are also sold asEUDRAGITS manufactured by Rohm Tech Inc., and neutral proteins.

[1214] A preferred subset of neutral polymers are those that are alsoconcentration-enhancing. Dispersion polymers that are both neutral andalso concentration-enhancing are generally amphiphilic in that theypossess substituents that are relatively hydrophobic and substituentsthat are relatively hydrophilic.

[1215] Amphiphilic cellulosics may be prepared by substituting thecellulose at any or all of the 3 hydroxyl substituents present on eachsaccharide repeat unit with at least one relatively hydrophobicsubstituent. Hydrophobic substituents may be essentially any substituentthat, if substituted to a high enough level or degree of substitution,can render the cellulosic polymer essentially aqueous insol-uble.Hydrophilic regions of the polymer can be either those portions that arerelatively unsubstituted, since the unsubstituted hydroxyls arethemselves relatively hydrophilic, or those regions that are substitutedwith hydrophilic substitu-ents. Examples of hydrophobic substitutentsinclude ether-linked alkyl groups such as methyl, ethyl, propyl, butyl,etc.; or ester-linked alkyl groups such as acetate, propionate,butyrate, etc.; and ether- and/or ester-linked aryl groups such asphenyl, benzoate, or phenylate. As discussed above, hydrophilicsubstituents may consist of non-acidic ionizable groups such asamino-functionalized groups or phenolate groups. In the case ofnon-ionizable neutral dispersion polymers, such hydrophilic groups arenon-ionizable substituents such as alcohol, ether or ester groups.

[1216] Exemplary amphiphilic polymers include non-ionizable cellulosicssuch as hydroxypropyl methyl cellulose, hydroxyethyl methyl celluloseand hydroxyethyl acetate; non-acidic ionizable cellulosics such as aminoethyl cellulose acetate and hydroxybenzyl cellulose; and non-ionizablenon-cellulosics such as polyvinylpyrrolidone ethylene/vinyl alcoholcopolymers and polyoxyethylene-polyoxypropylene block copolymers (alsoreferred to as poloxamers); and ionizable non-cellulosics such asamine-functionalized polyacrylates and polymethacrylates. When theamphiphilic polymer is hydroxypropyl methyl cellulose, it is preferredthat it is provided in a grade that possesses a dynamic viscosity thatis 60 mPa-s or less, more preferably 10 mPa-s or less and mostpreferably between 1 mPa-s and 6 mPa-s, when measured in a 2%weight/volume solution at 20° C.

[1217] A preferred class of neutral non-cellulosic polymers arecomprised of vinyl copolymers of a hydrophilic, hydroxyl-containingrepeat unit and a hydrophobic, alkyl- or aryl-containing repeat unit.Such neutral vinyl copolymers are termed “amphiphilichydroxyl-functional vinyl copolymers.” Amphiphilic hydroxyl-functionalvinyl copolymers are exceptional in that they are both non-ionic andyet, surprisingly, when used as dispersion polymers for low-solubilitydrugs, yield solid amorphous dispersions that provide high levels ofdrug concentration enhancement when dosed to an aqueous environment ofuse. Such polymers may be used with any low-solubility drug, and notsimply acid-sensitive drugs.

[1218] Dispersions of such copolymers are believed to provide highconcentration enhancements due to the amphiphilicity of these copolymerswhich provide both sufficient hydrophobic groups to interact with thehydrophobic, low-solubility drugs and also sufficient hydrophilic groupsto have sufficient aqueous solubility for good dissolution. Thecopolymeric structure of the amphiphilic hydroxyl-functional vinylcopolymers also allows their hydrophilicity and hydrophobicity to beadjusted to maximize performance with a specific low-solubility drug.

[1219] The preferred copolymers have the general structure:

[1220] wherein A and B represent “hydrophilic, hydroxyl-containing” and“hydrophobic” substituents, respectively, and n and m represent theaverage number of hydrophilic vinyl repeat units and average number ofhydrophobic vinyl repeat units respectively per polymer molecule.Copolymers may be block copolymers, random copolymers or they may havestructures anywhere between these two extremes. The sum of n and m isgenerally from about 50 to about 20,000 and therefore the polymers havemolecular weights from about 2,500 to about 1,000,000 daltons.

[1221] The hydrophilic, hydroxyl-containing repeat units, “A,” maysimply be hydroxyl (—OH) or it may be any short-chain, 1 to 6 carbon,alkyl with one or more hydroxyls attached thereto. Thehydroxyl-substituted alkyl may be attached to the vinyl backbone viacarbon-carbon or ether linkages. Thus, exemplary “A” structures include,in addition to hydroxyl itself, hydroxymethyl, hydroxyethyl,hydroxypropyl, hydroxymethoxy, hydroxyethoxy and hydroxypropoxy.

[1222] The hydrophobic substituent, “B,” may simply be: hydrogen (—H),in which case the hydrophobic repeat unit is ethylene; an alkyl or arylsubstituent with up to 12 carbons attached via a carbon-carbon bond suchas methyl, ethyl or phenyl; an alkyl or aryl substituent with up to 12carbons attached via an ether linkage such as methoxy, ethoxy orphenoxy; an alkyl or aryl substituent with up to 12 carbons attached viaan ester linkage such as acetate, propionate, butyrate or benzoate. Theamphiphilic hydroxyl-functional vinyl copolymers of the presentinvention may be synthesized by any conventional method used to preparesubstituted vinyl copolymers. Some substituted vinyl copolymers such aspolyvinyl alcohol/polyvinyl acetate are well known and commerciallyavailable.

[1223] A particularly convenient subclass of amphiphilichydroxyl-functional vinyl copolymers to synthesize are those where thehydrophobic substituent “B” comprises the hydrophilic substituent “A” towhich an alkylate or arylate group is attached via an ester link-age toone or more of the hydroxyls of A. Such copoly-mers may be synthesizedby first forming the homopolymer of the hydrophobic vinyl repeat unithaving the substi-tuent B, followed by hydrolysis of a portion of theester groups to convert a portion of the hydrophobic repeat units tohydrophilic, hydroxyl-containing repeat units having the substituent A.For example, partial hydrolysis of the homopolymer, polyvinylbutyrate,yields the copolymer, vinylalcohol/vinylbutyrate copolymer for which Ais hydroxyl (—OH) and B is butyrate (—OOC—CH₂₋CH₂₋CH₃).

[1224] For all types of copolymers, the value of n must be sufficientlylarge relative to the value of m that the resulting copolymer is atleast partially water soluble. Although the value of the ratio, n/mvaries depending on the identity of A and B, it is generally at leastabout 1 and more commonly about 2 or more. The ratio n/m can be as highas 200. When the copolymer is formed by hydrolysis of the hydrophobichomopolymer, the relative values of n and m are typically reported in“percent hydrolysis,” which is the fraction (expressed as a percent) ofthe total repeat units of the copolymer that are in the hydrolyzed orhydroxyl form. The percent hydrolysis, H, is given as

H=100*

[1225] $H = {100*\left( \frac{n}{n + m} \right)}$

[1226] Thus, vinylbutyrate/vinylalcohol copolymer (formed by hydrolysisof a portion of the butyrate groups) having a percent hydrolysis of 75%has an n/m ratio of 3.

[1227] A particularly preferred family of amphiphilichydroxyl-functional vinyl copolymers are those where A is hydroxyl and Bis acetate. Such copolymers are termed vinylacetate/vinylalcoholcopolymers. Some commercial grades are also sometimes referred to simplyas polyvinylalcohol. However, the true homopolymer, polyvinylalcohol isnot amphiphilic, is almost entirely water insoluble, and is not a partof this invention. Preferred vinylacetate/vinylalcohol copolymers arethose where H is between about 67% and 99.5%, or n/m has a value betweenabout 2 and 200. The preferred average molecular weight is between about2500 and 1,000,000 daltons and more preferably between about 3000 andabout 100,000 daltons.

[1228] In order to form dispersions that have a high level ofconcentration and bioavailability enhancement, it is important that theidentity of A and B, the n/m value, and average molecular weight bechosen such that the polymers are sufficiently hydrophobic that theystrongly interact with the hydrophobic, low-solubility drug and yet arestill significantly water soluble. Typically good results are obtainedwhen the aqueous solubility of the copolymer at 37° C. is between about0.04 and 10.0 wt % and preferably between about 0.1 and 2.0 wt %.

[1229] While specific polymers are discussed as being suitable for usein the compositions of the present invention, blends of such polymersmay also be suitable. Thus the term “polymer” is intended to includeblends of polymers in addition to a single species of polymer.

CONCENTRATION ENHANCEMENT

[1230] As described above, it is often preferred that the neutraldispersion polymer is also concentration-enhancing. The neutralconcentration-enhancing dispersion polymers improve the concentration ofa low-solubility drug in a use environment, and thereby preferablyimprove bioavailability of the drug.

[1231] The term “concentration-enhancing” means that the polymer ispresent in a sufficient amount in the composition so as to improve theconcentration of the drug in a use environment relative to a controlcomposition free from the concentration-enhancing polymer. As usedherein, a “use environment” can be either the in vivo environment of theGI tract, subdermal, intranasal, buccal, intrathecal, ocular,intraaural, subcutaneous spaces, vaginal tract, arterial and venousblood vessels, pulmonary tract or intramuscular tissue of an animal,such as a mammal and particularly a human, or the in vitro environmentof a test solution, such as phosphate buffered saline (PSB) or a ModelFasted Duodenal (MFD) solution. Concentration enhancement may bedetermined through either in vitro dissolution tests or through in vivotests. It has been determined that enhanced drug concentration in invitro dissolution tests in Model Fasted Duodenal (MFD) solution orPhosphate Buffered Saline (PBS) is a good indicator of in vivoperformance and bioavailability. An appropriate PBS solution is anaqueous solution comprising 20 mM sodium phosphate (Na₂HPO₄), 47 mMpotassium phosphate (KH₂PO₄), 87 mM NaCl, and 0.2 mM KCl, adjusted to pH6.5 with NaOH. An appropriate MFD solution is the same PBS solutionwherein additionally is present 7.3 mM sodium taurocholic acid and 1.4mM of 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine. In particular, acomposition containing a concentration-enhancing polymer may bedissolution-tested by adding it to MFD or PBS solution and agitating topromote dissolution.

[1232] In one aspect, a composition containing a concentration-enhancingpolymer of the present invention provides a Maximum Drug Concentration(MDC) that is at least 1.25-fold the MDC provided by a controlcomposition. In other words, if the MDC provided by the controlcomposition is 100 □g/mL, then a composition of the present inventioncontaining a concentration-enhancing polymer provides an MDC of at least125 □g/mL. More preferably, the MDC of drug achieved with thecompositions of the present invention are at least 2-fold, even morepreferably at least 3-fold, and most preferably at least 10-fold that ofthe control composition.

[1233] The appropriate control composition depends on whether adispersion polymer is being tested, or whether a composition comprisedof a mixture of a dispersion and concentration-enhancing polymer isbeing tested. Where the composition is simply the dispersion itself, andthe dispersion polymer is being tested to determine whether it is aconcentration-enhancing polymer, the control composition isconventionally the undispersed drug alone (e.g., typically, thecrystalline drug alone in its most thermodynamically stable crystallineform, or in cases where a crystalline form of the drug is unknown, thecontrol may be the amorphous drug alone) or the drug plus a weight ofinert diluent equivalent to the weight of polymer in the testcomposition. By inert is meant that the diluent is notconcentration-enhancing. Where the composition is comprised of a mixtureof a dispersion and additional concentration-enhancing polymer, thecontrol composition is the dispersion alone without any additionalconcentration-enhancing polymer.

[1234] Alternatively, the compositions containingconcentration-enhancing polymers of the present invention provide in anaqueous use environment a concentration versus time Area Under The Curve(AUC), for any period of at least 90 minutes between the time ofintroduction into the use environment and about 270 minutes followingintroduction to the use environment that is at least 1.25-fold that ofan appropriate control composition. More preferably, the AUC achievedwith the compositions of the present invention are at least 2-fold, morepreferably at least 3-fold, and most preferably at least 10-fold that ofa control composition.

[1235] Alternatively, the compositions of the present inventioncontaining concentration-enhancing polymers, when dosed orally to ahuman or other animal, provide an AUC in drug concentration in the bloodplasma or serum that is at least 1.25-fold that observed when anappropriate control composition is dosed. Preferably, the blood AUC isat least 2-fold, more preferably at least 3-fold, that of an appropriatecontrol composition. Thus, the compositions that, when evaluated, meeteither the in vitro or the in vivo, or both, performance criteria are apart of this invention.

[1236] A typical in vitro test to evaluate enhanced drug concentrationcan be conducted by (1) administering with agitation a sufficientquantity of test composition (for example, the dispersion of thelow-solubility drug and neutral polymer) in a test medium, such that ifall of the drug dissolved, the theoretical concentration of drug wouldexceed the equilibrium concentration of the drug by a factor of at least2; (2) adding an appropriate amount of control composition to anequivalent amount of test medium; and (3) determining whether themeasured MDC and/or AUC of the test composition in the test medium is atleast 1.25-fold that provided by the control composition. Theconcentration of dissolved drug is typically measured as a function oftime by sampling the test medium and plotting drug concentration in thetest medium vs. time so that the MDC and/or AUC can be ascertained. Inconducting such a dissolution test, the amount of test composition orcontrol composition used is an amount such that if all of the drugdissolved, the drug concentration would be at least 2-fold to 100-foldthat of the solubility (that is, the equilibrium concentration), of thedrug. For some dispersions of a very low-solubility drug and neutralpolymer, it may be necessary to administer an even greater amount of thedispersion to determine the MDC.

[1237] To avoid drug particulates which would give an erroneousdetermination, the test solution is either filtered or centrifuged.“Dissolved drug” is typically taken as that material that either passesa 0.45 μm syringe filter or, alternatively, the material that remains inthe supernatant following centrifugation. Filtration can be conductedusing a 13 mm, 0.45 μm polyvinylidine difluoride syringe filter sold byScientific Resources under the trademark TITAN®. Centrifugation istypically carried out in a polypropylene microcentrifuge tube bycentrifuging at 13,000 G for 60 seconds. Other similar filtration orcentrifugation methods can be employed and useful results obtained. Forexample, using other types of microfilters may yield values somewhathigher or lower (±10-40%) than that obtained with the filter specifiedabove but will still allow identification of preferred dispersions. Itis recognized that this definition of “dissolved drug” encompasses notonly monomeric solvated drug molecules but also a wide range of speciessuch as polymer/drug assemblies that have submicron dimensions such asdrug aggregates, aggregates of mixtures of polymer and drug, micelles,polymeric micelles, colloidal particles or nanocrystals, polymer/drugcomplexes, and other such drug-containing species that are present inthe filtrate or supernatant in the specified dissolution test.

[1238] Alternatively, the concentration-enhancing polymer results inimproved bioavailability. Relative bioavailability of the drug in thecompositions of the present invention can be tested in vivo in animalsor humans using conventional methods for making such a determination. Anin vivo test, such as a crossover study, may be used to determinewhether a composition provides an enhanced relative bioavailabilitycompared with a control. In an in vivo crossover study a “testcomposition” of drug and concentration-enhancing polymer is dosed tohalf a group of test subjects and, after an appropriate washout period(e.g., one week) the same subjects are dosed with a “controlcomposition” that comprises an equivalent quantity of drug as the “testcomposition.” The other half of the group is dosed with the controlcomposition first, followed by the test composition. The relativebioavailability is measured as the concentration in the blood (serum orplasma) versus time area under the curve (AUC) determined for the testcomposition divided by the AUC in the blood provided by the controlcomposition. Preferably, this test/control ratio is determined for eachsubject, and then the ratios are averaged over all subjects in thestudy. In vivo determinations of AUC can be made by plotting the serumor plasma concentration of drug along the ordinate (y-axis) against timealong the abscissa (x-axis). Generally, the values for AUC represent anumber of values taken from all of the subjects in a patient testpopulation averaged over the entire test population.

[1239] A preferred embodiment of the invention is one in which therelative bioavailability of the test composition is at least 1.25relative to a control composition as described above. (That is, the AUCin the blood provided by the test composition is at least 1.25-fold theAUC provided by the control composition.) An even more preferredembodiment of the invention is one in which the relative bioavailabilityof the test composition is at least 2.0, more preferably at least 3,relative to a control composition of the drug but with no polymerpresent, as described above. The determination of AUCs is a well-knownprocedure and is described, for example, in Welling, “PharmacokineticsProcesses and Mathematics,” ACS Monograph 185 (1986).

[1240] Often the enhancement in drug concentration or relativebioavailability that is observed increases as the drug:polymer ratiodecreases from a value of about 1 (50 wt % drug) to a value of about0.11 (10 wt % drug). The drug:polymer ratio that yields optimum resultsvaries from drug to drug and is best determined in in vitro dissolutiontests and/or in vivo bioavailability tests. However, the amount ofpolymer that can be used in a dosage form is often limited by the totalmass requirements of the dosage form. For example, when oral dosing to ahuman is desired, at low drug-to-polymer ratios the total mass of drugand polymer may be unacceptably large for delivery of the desired dosein a single tablet or capsule. Thus, it is often necessary to usedrug-to-polymer ratios that are less than optimum in specific dosageforms to provide a sufficient drug dose in a dosage form that is smallenough to be easily delivered to a use environment.

IMPROVED CHEMICAL STABILITY

[1241] When the compositions of the present invention comprisedispersions of acid-sensitive drug and neutral polymer(s), suchcompositions provide improved chemical stability of the drug relative toa control composition comprised of an equivalent quantity of drugdispersed in an acidic dispersion polymer. The acidic dispersion polymerused in the control composition may be any polymer suitable fordetermining whether the drug is acid-sensitive that meets the definitionof an “acidic polymer.” Convenient acidic dispersion polymers for use inthe control composition include HPMCAS, CAP and HPMCP. A composition ofthe present invention will meet the chemical stability requirementsdiscussed below relative to at least one control dispersion of drug andeither HPMCAS, HPMCP, or CAP.

[1242] A relative degree of improvement in chemical stability of anacid-sensitive drug in a test composition may be determined by takingthe ratio of the degree of degradation of the drug in a controlcomposition and the degree of degradation of the drug in a testcomposition under the same storage conditions for the same storage timeperiod. The test composition is simply the composition of acid-sensitivedrug, neutral polymer and optional additional excipients of the presentinvention. The control composition is the same as the test compositionwith the exception that an acidic dispersion polymer (that is, eitherHPMCAS, HPMCP or CAP) replaces the neutral dispersion polymer. Forexample, where the degree of degradation of a drug in a test compositioncomprised of an acid-sensitive drug and a neutral polymer is 1 wt %, andthe degree of degradation of a control composition comprised of anequivalent quantity of drug and HPMCAS is 5 wt %, the relative degree ofimprovement is 5 wt %/1 wt % equals 5.0. For dispersions ofacid-sensitive drugs and neutral polymers of the present invention, therelative degree of improvement is at least 1.25. Preferably, therelative degree of improvement is at least 3, more preferably at least5, and even more preferably at least 10. In fact, some compositions ofthe present invention may achieve a relative degree of improvementgreater than 100.

[1243] The particular storage conditions and time of storage may bechosen as convenient depending on the degree of acid-sensitivity of thedrug, the particular acidic polymer used in the control dispersion, andthe ratio of drug to polymer in the dispersion. Where the drug isparticularly acid-sensitive, or where the dispersion has a low ratio ofdrug to polymer, then shorter storage time periods may be used. Wherethe rate of drug degradation is linear, the relative degree ofimprovement will be independent of the storage time. However, where therate of drug degradation is non-linear under controlled storageconditions, the stability test used to compare the test dispersion withthe control dispersion is preferably chosen such that the degree ofdegradation is sufficiently large that it may be accurately measured.Typically, the time period is chosen so as to observe a degree ofdegradation in the control composition of at least 0.1 wt % to 0.2 wt %.However, the time period is not so long that the ratio of drug topolymer changes substantially. Typically, the time period is such thatthe observed degree of degradation for the test composition is less than50 wt % and preferably less than 20 wt %. When rate of drug degradationin the control composition is relatively slow, the test is preferablyconducted over a long enough period of time under controlled storageconditions to allow a meaningful comparison of the stability of the testdispersion with the control dispersion.

[1244] A stability test which may be used to test whether a dispersionmeets the chemical stability criteria described above is storage of thetest dispersion and the control dispersion for six months at 40° C. and75% RH. A relative degree of improvement may become apparent within ashorter time, such as three to five days, and shorter storage times maybe used for some very acid-sensitive drugs. When comparing dispersionsunder storage conditions which approximate ambient conditions, e.g., 30°C. and 60% RH, the storage period may need to be several months up totwo years.

[1245] In addition, it is preferred that the dispersions comprisingacid-sensitive drug and neutral polymer(s) result in drug stability suchthat the acid-sensitive drug has a degree of degradation of less thanabout 2 wt %, more preferably less than about 0.5 wt %, and mostpreferably less than about 0.1 wt % when stored at 40° C. and 75% RH forsix months, or less than 2 wt %, more preferably 0.5 wt %, and morepreferably 0.1 wt %, when stored at 30° C. and 60% RH for one year.Nevertheless, the compositions of the present invention may have adegree of degradation that is much greater than the preferred values, solong as the dispersion achieves the degree of improvement relative to acontrol composition as described above.

PREPARATION OF DISPERSIONS

[1246] Dispersions of the drugs and neutral dispersion polymer may bemade according to any known process which results in at least a “majorportion” (meaning at least 60 wt %) of the drug being in the amorphousstate. Such processes include mechanical, thermal and solvent processes.Exemplary mechanical processes include milling and extrusion; meltprocesses include high temperature fusion, solvent modified fusion andmelt-congeal processes; and solvent processes include non-solventprecipitation, spray coating and spray-drying. See, for example, U.S.Pat. No. 5,456,923 and U.S. Pat. No. 5,939,099 which describe formationof dispersions via extrusion processes; U.S. Pat. No. 5,340,591 and U.S.Pat. No. 4,673,564 which describe forming dispersions by millingprocesses; and U.S. Pat. No. 5,707,646 and U.S. Pat. No. 4,894,235 whichdescribe the formation of dispersions via melt/congeal processes, thedisclosures of which are incorporated by reference.

[1247] While the drug in its pure state may be crystalline or amorphous,at least a major portion of the drug in the dispersion is amorphous. By“amorphous” is meant simply that the drug is in a non-crystalline state.As used herein, the term “a major portion” of the drug means that atleast 60% of the drug in the dispersion is in the amorphous form, ratherthan the crystalline form. In general, a drug is more reactive in itsamorphous state relative to its crystalline state and so the need to usea neutral dispersion polymer to prevent degradation of acid-sensitvesensitive drug increases as the fraction of drug in the amorphous stateincreases. It has also been found that the aqueous concentration of thedrug in a use environment tends to improve as the fraction of drugpresent in the amorphous state in the dispersion increases. Accordingly,a “major portion” of the drug in the dispersion is amorphous andpreferably the drug in the dispersion is substantially amorphous. Asused herein, a “major portion” and “substantially amorphous” mean thatthe amount of the drug in crystalline form does not exceed about 40 wt %and about 25 wt %, respectively. More preferably, the drug in thedispersion is “almost completely amorphous,” meaning that the amount ofdrug in the crystalline form does not exceed 10 wt %. Amounts ofcrystalline drug may be measured by powder X-ray diffraction, ScanningElectron Microscope (SEM) analysis, differential scanning calorimetry(DSC), or any other standard quantitative measurement.

[1248] The amorphous drug can exist as a pure phase, as a solid solutionof drug homogeneously distributed throughout the polymer or anycombination of these states or those states that lie intermediatebetween them. In cases where the drug is a low-solubility drug andconcentration or bioavailability enhancement is desired, the dispersionis preferably “substantially homogeneous” so that the amorphous drug isdispersed as homogeneously as possible throughout the polymer.Dispersions of the present invention that are substantially homogeneousgenerally are more physically stable and have improvedconcentration-enhancing properties and, in turn improvedbioavailability, relative to nonhomogeneous dispersions. As used herein,“substantially homogeneous” means that the drug present in relativelypure amorphous domains within the solid dispersion is relatively small,on the order of less than 20%, and preferably less than 10% of the totalamount of drug.

[1249] While the dispersion may have some drug-rich domains, it ispreferred that the dispersion itself have a single glass transitiontemperature (T_(g)) which demonstrates that the dispersion issubstantially homogeneous. This contrasts with a simple physical mixtureof pure amorphous drug particles and pure amorphous polymer particleswhich generally display two distinct T_(g)s, one that of the drug andone that of the polymer. T_(g) as used herein is the characteristictemperature where a glassy material, upon gradual heating, undergoes arelatively rapid (e.g., 10 to 100 seconds) physical change from a glassstate to a rubber state. Almost completely amorphous, substantiallyhomogeneous dispersions may be made by any of the processes discussedabove.

[1250] To obtain the maximum level of concentration and bioavailabilityenhancement, particularly upon storage for long times prior to use, itis preferred that the drug remain, to the extent possible, in theamorphous state. The inventors have found that this is best achievedwhen the glass-transition temperature, T_(g), of the amorphousdispersion is substantially above the storage temperature of thedispersion. In particular, it is preferable that the T_(g) of theamorphous dispersion is at least 40° C. and preferably at least 60° C.Since the T_(g) is a function of the water content of the dispersionwhich in turn is a function of the RH to which the dispersion isexposed, these T_(g) values refer to the T_(g) of the dispersioncontaining water in an amount that is in equilibrium with the RHequivalent to that found during storage. For those aspects of theinvention in which the dispersion is a solid, substantially amorphousdispersion of drug in the dispersion polymer and in which the drugitself has a relatively low T_(g) (about 70° C. or less) it is preferredthat the dispersion polymer have a T_(g) of at least 40° C., preferablyat least 70° C. and more preferably greater than 100° C. Exemplary highT_(g) polymers include hydroxypropyl cellulose and hydroxypropyl methylcellulose. Since conversion of amorphous drug to the crystalline stateis related to the relative values of (1) the T_(g) of the dispersion (atthe storage RH) and (2) the storage temperature, solid amorphousdispersions of the present invention may tend to remain in the amorphousstate for longer periods when stored at relatively low temperatures andlow relative humidities. In addition, packaging of such dispersions soas to prevent absorption of water or inclusion of a water absorbingmaterial such as a dessicant to also prevent or retard water absorptioncan lead to a higher T_(g) during storage, thereby helping to retain theamorphous state. Likewise, storage at lower temperatures can alsoimprove the retention of the amorphous state.

[1251] Turning now to particular methods, when either the neutralpolymer or the drug has a relatively low melting point, typically lessthan about 200° C. and preferably less than about 160° C., extrusion ormelt-congeal processes that provide heat and/or mechanical energy areoften suitable for forming almost completely amorphous dispersions.Often, when the drug has significant solubility in the dispersionmaterial, such methods may also make substantially homogeneousdispersions. For example, 10 wt % drug and 90 wt % polyvinyl pyrrolidone(PVP) may be dry blended, with or without the addition of water, and theblend fed to a twin-screw extrusion device. The processing temperaturemay vary from about 50° C. up to about 200° C. depending on the meltingpoint of the drug and polymer, which is a function of the polymer gradechosen and the amount of water, if any, added. Generally, the higher themelting point of the drug and polymer, the higher the processingtemperature. Generally, the lowest processing temperature that producesa satisfactory dispersion (almost completely amorphous and substantiallyhomogeneous) is chosen.

[1252] A method for forming dispersions that is often preferred is“solvent processing,” which consists of dissolution of the drug and oneor more neutral polymers in a common solvent. The term “solvent” is usedbroadly and includes mixtures of solvents. “Common” here means that thesolvent, which can be a mixture of compounds, will simultaneouslydissolve both the drug and the polymer(s).

[1253] After both the drug and polymer(s) have been dissolved, thesolvent is removed by evaporation or by mixing with a non-solvent.Exemplary processes are spray-drying, spray-coating (pan-coating,fluidized bed coating, etc.), vacuum evaporation, precipitation bymixing of the polymer and drug solution with a non-solvent such as CO₂,hexane, or heptane, and processes that combine solvents with heat andmechanical energy such as extrusion processes that include the use of asolvent as a processing aid or even wet granulation processes as long assuch processes result in at least a major portion of the drug beingamorphous. Preferably, removal of the solvent is rapid and results in asolid dispersion which is substantially homogeneous. In substantiallyhomogeneous dispersions, the drug is dispersed as homogeneously aspossible throughout the polymer and can be thought of as a solidsolution of drug dispersed in the polymer(s). When the resultingdispersion constitutes a solid solution of drug in polymer, thedispersion may be thermodynamically stable, meaning that theconcentration of drug in the polymer is at or below its equilibriumvalue, or it may be considered a supersaturated solid solution where thedrug concentration in the dispersion polymer(s) is above its equilibriumvalue.

[1254] The solvent may be removed through the process of spray-drying.The term spray-drying is used conventionally and broadly refers toprocesses involving breaking up liquid mixtures into small droplets(atomization) and rapidly removing solvent from the mixture in acontainer (spray-drying apparatus) where there is a strong driving forcefor evaporation of solvent from the droplets. The strong driving forcefor solvent evaporation is generally provided by maintaining the partialpressure of solvent in the spray-drying apparatus well below the vaporpressure of the solvent at the temperature of the drying droplets. Thisis accomplished by either (1) maintaining the pressure in thespray-drying apparatus at a partial vacuum (e.g., 0.01 to 0.50 atm); (2)mixing the liquid droplets with a warm drying gas; or (3) both. Inaddition, at least a portion of the heat required for evaporation ofsolvent may be provided by heating the spray solution.

[1255] Solvents suitable for spray-drying can be any organic compound inwhich the drug and polymer are mutually soluble. Preferably, the solventis also volatile with a boiling point of 150° C. or less. In addition,the solvent should have relatively low toxicity and be removed from thedispersion to a level that is acceptable according to The InternationalCommittee on Harmonization (ICH) guidelines. Removal of solvent to thislevel may require a processing step such as tray-drying or fluidized-beddrying subsequent to the spray-drying or spray-coating process.Preferred solvents include alcohols such as methanol, ethanol,n-propanol, iso-propanol, and butanol; ketones such as acetone, methylethyl ketone and methyl iso-butyl ketone; esters such as ethyl acetateand propylacetate; and various other solvents such as acetonitrile,methylene chloride, toluene, and 1,1,1-trichloroethane. Lower volatilitysolvents such as dimethyl acetamide or dimethylsulfoxide can also beused. Mixtures of solvents, such as 50% methanol and 50% acetone, canalso be used, as can mixtures with water as long as the polymer and drugare sufficiently soluble to make the spray-drying process practicable.In particular, when the neutral polymer is relatively hydrophilic suchas hydroxypropyl methyl cellulose (HPMC), or certain amphiphilichydroxyl-functional vinyl copolymers, it is often preferred to use amixture of an organic solvent and water to ensure that both drug andpolymer are simultaneously soluble.

[1256] Generally, the temperature and flow rate of the drying gas ischosen so that the polymer/drug-solution droplets are dry enough by thetime they reach the wall of the apparatus that they are essentiallysolid, and so that they form a fine powder and do not stick to theapparatus wall. The actual length of time to achieve this level ofdryness depends on the size of the droplets. Droplet sizes generallyrange from 1 □m to 500 □m in diameter, with 5 to 200 □m being moretypical. The large surface-to-volume ratio of the droplets and the largedriving force for evaporation of solvent leads to actual drying times ofa few seconds or less, and more typically less than 0.1 second. Thisrapid drying is often critical to the particles maintaining a uniform,homogeneous dispersion instead of separating into drug-rich andpolymer-rich phases. As above, to get large enhancements inconcentration and bioavailability it is often necessary to obtain ashomogeneous of a dispersion as possible. Solidification times should beless than 100 seconds, preferably less than a few seconds, and morepreferably less than 1 second. In general, to achieve this rapidsolidification of the drug/polymer solution, it is preferred that thesize of droplets formed during the spray-drying process are less thanabout 500 □m in diameter, and preferably less than about 300 □m. Theresultant solid particles thus formed are generally less than about 300□m in diameter.

[1257] Following solidification, the solid powder typically stays in thespray-drying chamber for about 5 to 60 seconds, further evaporatingsolvent from the solid powder. The final solvent content of the soliddispersion as it exits the dryer should be low, since this reduces themobility of drug molecules in the dispersion, thereby improving itsstability. Generally, the solvent content of the dispersion as it leavesthe spray-drying chamber should be less than about 10 wt % andpreferably less than about 3 wt %. In some cases, it may be preferableto spray a solvent or a solution of a polymer or other excipient intothe spray-drying chamber to form granules, so long as the dispersion isnot adversely affected.

[1258] Spray-drying processes and spray-drying equipment are describedgenerally in Perry's Chemical Engineers' Handbook, Sixth Edition (R. H.Perry, D. W. Green, J. O. Maloney, eds.) McGraw-Hill Book Co. 1984,pages 20-54 to 20-57. More details on spray-drying processes andequipment are reviewed by Marshall “Atomization and Spray-Drying,” 50Chem. Eng. Prog. Monogr. Series 2 (1954).

[1259] The solid amorphous dispersions formed from a low-solubility drugand an amphiphilic hydroxyl-functional vinyl copolymer are preferablyalmost completely amorphous and substantially homogenous. Such almostcompletely amorphous, substantially homogenous dispersions are generallymore physically stable (that is, resist phase separation orcrystallization upon storage), and show higher levels of concentrationenhancement. As with the dispersions of other embodiments of theinvention, such dispersions may in principle be formed by any knownprocess, including mechanical, thermal and solvent processes. However,“solvent processing” is preferred for forming dispersions of amphiphilichydroxyl-functional vinyl copolymers because when properly performed,solvent processing tends to produce dispersions in which the drug isalmost completely amorphous and in which the dispersion is substantiallyhomogeneous.

[1260] In order to achieve such preferred dispersions, a copolymer typeand solvent must be chosen to yield a solution in which the amphiphilic,hydroxyl-functional vinyl copolymer and low-solubility drug are bothsoluble and preferably highly soluble. Preferably, both the copolymerand low-solubility drug each have solubilities in the solvent at 37° C.of at least 0.5 wt % and preferably at least 2.0 wt % and morepreferably at least 5.0 wt %.

[1261] In order to have the drug and copolymer both have such highsolubilities in the solvent while the polymer is also sufficientlysoluble in aqueous solution, the polymer molecular weight must generallynot be too high and the polymer must have the correct n/m values. Forexample it has been found that for vinylacetate/vinylalcohol copolymersthat n/m values are preferably between about 2 and 100 and molecularweights are preferably less than about 50,000 daltons.

[1262] In addition, the solvent is preferably chosen such that thelesser of either (1) the polymer solubility or (2) the product of thedrug solubility and the ratio of the polymer to drug in the finaldispersion, is high and is preferably maximized. To achieve this, it isoften desirable to use blends of two or more solvents. In particular, ablend of water and an organic solvent is often preferred. Exemplarypreferred solvents are mixtures of water and alcohols such as methanol,ethanol, n-propanol, iso-propanol and the isomers of butanol.

[1263] In addition it is preferable for the solvent processing to beconducted such that solvent is removed rapidly so that the polymer-drugsolution solidifies rapidly. Thus solvent processes such asspray-coating and spray-drying are preferred.

[1264] In addition, to achieve rapid solvent removal, and to keep theresidual solvent level in the dispersion low (preferably less than about5 wt %), a relatively volatile solvent is chosen. Preferably the boilingpoints of the solvents are less than about 150° C. and more preferablyless than about 125° C. When the solvent is a mixture of solvents, up toabout 40% of the solvent may comprise a low volatility solvent. When thedispersion polymer is a vinylacetate/vinylalcohol copolymer of thepreferred type described earlier, preferred solvents include mixtures ofmethanol and water.

[1265] Returning to dispersions generally, the amount of polymerrelative to the amount of drug present in the dispersions of the presentinvention depends on the drug and polymer and may vary widely from adrug-to-polymer weight ratio of from 0.01 to about 4 (e.g., 1 wt % drugto 80 wt % drug). However, in most cases it is preferred that thedrug-to-polymer ratio is greater than about 0.05 (4.8 wt % drug) andless than about 2.5 (71 wt % drug).

[1266] In addition to the drug and polymer(s), the dispersions of thepresent invention may include optional additional ingredients. Oneoptional additional ingredient is a buffer. Buffers suitable for use inthe dispersions of the present invention are preferably basic. Buffersare particularly preferred for dispersions of neutral polymers and drugsthat have a high degree of acid-sensitivity. The buffers may reduce therisk of drug degradation due to the presence of acidic species in thedispersion, elsewhere in the composition, or acidic or basic speciesformed during storage. The compositions preferably provide improvedchemical stability relative to dispersions that are free from thebuffer.

[1267] Exemplary buffers that may be used in the dispersions of thepresent invention include sodium acetate, ammonium acetate, sodiumcarbonate, sodium bicarbonate, disodium hydrogen phosphate and trisodiumphosphate. It is generally preferred that the buffer be chosen such thatit maintains the pH at the optimum value during storage to minimizedegradation reactions. For most acid-sensitive drugs, the preferred pHvalue is greater than about 6. Since many dispersion polymers such ascellulosics are also base-sensitive, it is generally preferred that thebuffer be chosen to maintain the dispersion pH between about 6 and 10.In cases where the acid-sensitive drug is also a base-sensitive drug, itis often preferred to maintain the dispersion pH between about 6 andabout 8. To accomplish this, it is sometimes desirable for the buffer tobe a blend of protonated and deprotonated material, where the pK_(a) ofthe protonated material is near the desired dispersion pH. Such buffersmay comprise from 0.1 to 20 wt % of the dispersion.

[1268] Alternatively, the dispersion may include basic excipients suchas mono-, di- or tri-ethanolamine, or glucoseamine, which may comprisefrom 0.1 to 20 wt % of the dispersion. Such basic excipients may be usedto control the dispersion pH as described above.

MIXTURES OF DISPERSIONS AND CONCENTRATION-ENHANCING POLYMER

[1269] A separate embodiment of the invention comprises a combination of(1) a dispersion of an acid-sensitive, low-solubility drug and neutraldispersion polymer(s) and (2) a second polymer that isconcentration-enhancing. The dispersion is free from at least a portionof the second polymer, and is preferably substantially free from thesecond polymer. By “substantially free” is meant that the dispersion andthe second polymer are not mixed at the molecular level to form adispersion containing the second polymer. While a small amount of thesecond polymer may be incorporated into the dispersion as a result ofprocessing, nevertheless the drug in the dispersion meets the chemicalstability requirements discussed above for dispersions of acid-sensitivedrugs and neutral polymers notwithstanding the presence of the secondpolymer in the composition. The neutral dispersion polymer optionallymay also be concentration-enhancing.

[1270] The compositions of this aspect of the present invention aregenerally physical combinations comprising the dispersion and the secondpolymer. “Combination” as used herein means that the dispersion andsecond polymer may be in physical contact with each other or in closeproximity but without the necessity of being physically mixed at themolecular level (i.e., a dispersion). The dispersion andconcentration-enhancing polymer may be in different regions of thecomposition. For example, the solid composition may be in the form of amulti-layer tablet, as known in the art, wherein one or more layerscomprises the dispersion and one or more different layers comprises thesecond polymer. Yet another example may constitute a coated tabletwherein either the dispersion or the second polymer or both may bepresent in the tablet core and the coating may comprise the secondpolymer. Alternatively, the combination can be in the form of a simpledry physical mixture wherein both the dispersion and the second polymerare mixed in particulate form and wherein the particles of each,regardless of size, retain the same individual physical properties thatthey exhibit in bulk. Any conventional method used to mix the dispersionand second polymer together such as physical mixing and dry or wetgranulation, which does not convert the dispersion and the secondpolymer to another molecular dispersion, may be used.

[1271] Alternatively, the dispersion and second polymer may beco-administered, meaning that the dispersion may be administeredseparately from, but within the same general time frame as, the secondpolymer. Thus, a dispersion may, for example, be administered in its owndosage form which is taken at approximately the same time as the secondpolymer which is in a separate dosage form. If administered separately,it is generally preferred to administer both the dispersion and thesecond polymer within 60 minutes of each other, so that the two arepresent together in the use environment. When not administeredapproximately simultaneously (e.g., within a minute or two of eachother), the second polymer is preferably administered prior to thedispersion.

[1272] The second polymer may be any concentration-enhancing polymer,such as those described above in connection with the neutral dispersionpolymers. As described above, the inventors have found that ionizable,cellulosic polymers, particularly those that are acidic cellulosicenteric polymers, provide superior enhancement in aqueous concentrationof the drug in a use environment relative to other polymers, and aretherefore preferred in the absence of their reactivity with the drug.Many of these ionizable, cellulosic polymers have acidic functionalgroups and therefore are inappropriate for use as a dispersion polymerwith acid-sensitive drugs. However, the concentration-enhancingadvantage provided by such ionizable concentration-enhancing polymersmay be achieved by simply combining such a polymer as the second polymerwith a pre-formed dispersion of the acid-sensitive drug and a neutralpolymer in a fashion that does not alter the neutral characteristic ofthe pre-formed dispersion.

[1273] A preferred class of concentration-enhancing polymers suitablefor use as the second polymer comprises ionizable cellulosic polymerswith at least one ester- and/or ether- linked substituent in which thepolymer has a degree of substitution of at least 0.05 for eachsubstituent. Particularly preferred hydrophilic substituents for use inmaking ionizable polymers are those that are ether- or ester-linkedacidic ionizable groups such as carboxylic acids, thiocarboxylic acidsand sulfonates, and groups that may be non-acidic such as substitutedphenoxy groups, amines, and phosphates. Exemplary ether-linked ionizablesubstituents include: carboxylic acids, such as acetic acid, propionicacid, benzoic acid, salicylic acid, alkoxybenzoic acids such asethoxybenzoic acid or propoxybenzoic acid, the various isomers ofalkoxyphthalic acid such as ethoxyphthalic acid and ethoxyisophthalicacid, the various isomers of alkoxynicotinic acid such asethoxynicotinic acid, and the various isomers of picolinic acid such asethoxypicolinic acid, etc.; thiocarboxylic acids, such as thioaceticacid; substituted phenoxy groups, such as hydroxyphenoxy, etc.; amines,such as aminoethoxy, diethylaminoethoxy, trimethylaminoethoxy, etc.;phosphates, such as phosphate ethoxy; and sulfonates, such as sulphonateethoxy. Exemplary ester linked ionizable substituents include:carboxylic acids, such as succinate, citrate, phthalate, terephthalate,isophthalate, trimellitate, and the various isomers ofpyridinedicarboxylic acid, etc.; thiocarboxylic acids, such asthiosuccinate; substituted phenoxy groups, such as amino salicylic acid;amines, such as natural or synthetic amino acids, such as alanine orphenylalanine; phosphates, such as acetyl phosphate; and sulfonates,such as acetyl sulfonate. For aromatic-substituted polymers to also havethe requisite aqueous solubility, it is also desirable that sufficienthydrophilic groups such as hydroxypropyl or carboxylic acid functionalgroups be attached to the polymer to render the polymer aqueous solubleat least at pH values where any ionizable groups are ionized. In somecases, the aromatic group may itself be ionizable, such as phthalate ortrimellitate substituents.

[1274] Exemplary ionizable cellulosic concentration-enhancing polymersthat are at least partially ionized at physiologically relevant pHsinclude: hydroxypropyl methyl cellulose acetate succinate, hydroxypropylmethyl cellulose succinate, hydroxypropyl cellulose acetate succinate,hydroxyethyl methyl cellulose succinate, hydroxyethyl cellulose acetatesuccinate, hydroxypropyl methyl cellulose phthalate, hydroxyethyl methylcellulose acetate succinate, hydroxyethyl methyl cellulose acetatephthalate, carboxyethyl cellulose, carboxymethyl cellulose, celluloseacetate phthalate, methyl cellulose acetate phthalate, ethyl celluloseacetate phthalate, hydroxypropyl cellulose acetate phthalate,hydroxypropyl methyl cellulose acetate phthalate, hydroxypropylcellulose acetate phthalate succinate, hydroxypropyl methyl celluloseacetate succinate phthalate, hydroxypropyl methyl cellulose succinatephthalate, cellulose propionate phthalate, hydroxypropyl cellulosebutyrate phthalate, cellulose acetate trimellitate, methyl celluloseacetate trimellitate, ethyl cellulose acetate trimellitate,hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate trimellitate, hydroxypropyl cellulose acetatetrimellitate succinate, cellulose propionate trimellitate, cellulosebutyrate trimellitate, cellulose acetate terephthalate, celluloseacetate isophthalate, cellulose acetate pyridinedicarboxylate, salicylicacid cellulose acetate, hydroxypropyl salicylic acid cellulose acetate,ethylbenzoic acid cellulose acetate, hydroxypropyl ethylbenzoic acidcellulose acetate, ethyl phthalic acid cellulose acetate, ethylnicotinic acid cellulose acetate, and ethyl picolinic acid celluloseacetate.

[1275] Another class of concentration-enhancing polymers suitable foruse with the present invention comprises ionizable non-cellulosicpolymers. Exemplary polymers of this type that are generally acidicinclude carboxylic acid-functionalized vinyl polymers, such as thecarboxylic acid functionalized polymethacrylates and carboxylic acidfunctionalized polyacrylates such as the EUDRAGITS® manufactured by RohmTech Inc., of Maiden, Mass., and acidic proteins.

[1276] A preferred class of concentration-enhancing polymers comprisespolymers that are “amphiphilic” in nature, meaning that the polymer hashydrophobic and hydrophilic portions. The hydrophobic portion maycomprise groups such as aliphatic or aromatic hydrocarbon groups. Thehydrophilic portion may comprise either ionizable or non-ionizablegroups that are capable of hydrogen bonding such as hydroxyls,carboxylic acids, esters, amines or amides.

[1277] Amphiphilic polymers are preferred because it is believed thatsuch polymers may tend to have relatively strong interactions with thedrug and may promote the formation of various types of polymer/drugassemblies in the use environment. Ionizable polymers, and particularlythose that have a significant level of carboxylic acid functional groups(e.g., acidic polymers) typically show the greatest concentration andbioavailability enhancements and therefore are preferred for use withlow-solubility drugs. However, they may not form a part of thedispersion when the drug is acid-sensitive. Thus, a particularlypreferred composition is one in which an acid-sensitive drug isdispersed in a neutral or non-ionizable polymer and an ionizable oracidic polymer is added such that it is not part of the dispersion.

[1278] In addition, ionic, and in particular acidic polymers, arethought to show desirable concentration-enhancement properties due tothe repulsion of the like charges of the ionized groups of suchpolymers. This repulsion may serve to limit the size of the polymer/drugassemblies to the nanometer or submicron scale. For example, while notwishing to be bound by a particular theory, such polymer/drug assembliesmay comprise hydrophobic drug clusters surrounded by the polymer withthe polymer's hydrophobic regions turned inward towards the drug and thehydrophilic regions of the polymer turned outward toward the aqueousenvironment. Alternatively, depending on the specific chemical nature ofthe drug, the ionized functional groups of the polymer may associate,for example, via ion pairing or hydrogen bonds, with ionic or polargroups of the drug. In the case of ionizable polymers, the hydrophilicregions of the polymer would include the ionized functional groups. Suchpolymer/drug assemblies in solution may well resemble charged polymericmicellar-like structures. In any case, regardless of the mechanism ofaction, the inventors have observed that such amphiphilic polymers,particularly ionizable cellulosic polymers, have been shown to improvethe maximum drug concentration (MDC) and/or area under the curve (AUC)of the drug in aqueous solution relative to control compositions freefrom such polymers.

[1279] Surprisingly, such amphiphilic polymers can greatly enhance themaximum concentration of drug obtained when the drug is dosed to a useenvironment. In addition, such amphiphilic polymers may interact withthe drug to prevent the precipitation or crystallization of the drugfrom solution despite its concentration being substantially above itsequilibrium concentration.

[1280] Exemplary ionizable cellulosic polymers that meet the definitionof amphiphilic, having hydrophilic and hydrophobic regions, includepolymers such as cellulose acetate phthalate and cellulose acetatetrimellitate where the cellulosic repeat units that have one or moreacetate substituents are hydrophobic relative to those that have noacetate substituents or have one or more ionized phthalate ortrimellitate substituents.

[1281] A particularly desirable subset of cellulosic ionizableconcentration-enhancing polymers are those that possess both acarboxylic acid functional aromatic substituent and an alkylatesubstituent and thus are amphiphilic. Exemplary polymers includecellulose acetate phthalate, methyl cellulose acetate phthalate, ethylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate,hydroxylpropyl methyl cellulose phthalate, hydroxypropyl methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalatesuccinate, cellulose propionate phthalate, hydroxypropyl cellulosebutyrate phthalate, cellulose acetate trimellitate, methyl celluloseacetate trimellitate, ethyl cellulose acetate trimellitate,hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate trimellitate, hydroxypropyl cellulose acetatetrimellitate succinate, cellulose propionate trimellitate, cellulosebutyrate trimellitate, cellulose acetate terephthalate, celluloseacetate isophthalate, cellulose acetate pyridinedicarboxylate, salicylicacid cellulose acetate, hydroxypropyl salicylic acid cellulose acetate,ethylbenzoic acid cellulose acetate, hydroxypropyl ethylbenzoic acidcellulose acetate, ethyl phthalic acid cellulose acetate, ethylnicotinic acid cellulose acetate, and ethyl picolinic acid celluloseacetate.

[1282] Another particularly desirable subset of cellulosic ionizablepolymers are those that possess a non-aromatic carboxylate substituent.Exemplary polymers include hydroxypropyl methyl cellulose acetatesuccinate, hydroxypropyl methyl cellulose succinate, hydroxypropylcellulose acetate succinate, hydroxyethyl methyl cellulose acetatesuccinate, hydroxyethyl methyl cellulose succinate, and hydroxyethylcellulose acetate succinate.

[1283] Non-cellulosic polymers that are amphiphilic are copolymers of arelatively hydrophilic and a relatively hydrophobic monomer. Examplesinclude acrylate and methacrylate copolymers. Exemplary commercialgrades of such copolymers include the EUDRAGITS, which are copolymers ofmethacrylates and acrylates. Another suitable class of amphiphiliccopolymers are the amphiphilic hydroxyl-functional vinyl copolymersdescribed previously.

EXCIPIENTS AND DOSAGE FORMS

[1284] Although the key ingredients present in the compositions of thepresent invention are simply the dispersion and optional non-dispersionconcentration-enhancing polymer(s), the inclusion of other excipients inthe composition may be useful. These excipients may be utilized with thedrug and polymer composition in order to formulate the composition intotablets, capsules, suppositories, suspensions, powders for suspension,creams, transdermal patches, depots, and the like. The composition ofdrug and polymer can be added to other dosage form ingredients inessentially any manner that does not substantially alter the drug. Theexcipients may be either physically mixed with the dispersion and/orincluded within the dispersion. However, where the drug isacid-sensitive, acidic excipients should not be added to the dispersionunless neutralized.

[1285] One very useful class of excipients is surfactants. Suitablesurfactants include fatty acid and alkyl sulfonates; commercialsurfactants such as benzalkonium chloride (HYAMINE® 1622, available fromLonza, Inc., Fairlawn, N.J.); dioctyl sodium sulfosuccinate, DOCUSATESODIUM™ (available from Mallinckrodt Spec. Chem., St. Louis, Mo.);polyoxyethylene sorbitan fatty acid esters (TWEEN®, available from ICIAmericas Inc., Wilmington, Del.; LIPOSORB® P-20 available from LipochemInc., Patterson N.J.; CAPMUL® POE-0 available from Abitec Corp.,Janesville, Wis.), and natural surfactants such as sodium taurocholicacid, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, lecithin, andother phospholipids and mono- and diglycerides. Preferably, thesurfactants are not acidic. In cases where the surfactant is acidic,such as fatty acids, the salts of the acids are preferred. Thus, sodiumdodecanate is preferred relative to dodecanoic acid. Such materials canadvantageously be employed to increase the rate of dissolution byfacilitating wetting, thereby increasing the maximum dissolvedconcentration, and also to inhibit crystallization or precipitation ofdrug by interacting with the dissolved drug by mechanisms such ascomplexation, formation of inclusion complexes, formation of micelles oradsorbing to the surface of solid drug, crystalline or amorphous. Thesesurfactants may comprise up to 5 wt % of the composition.

[1286] The addition of pH modifiers such as acids, bases, or buffers mayalso be beneficial, retarding the dissolution of the composition (e.g.,acids such as citric acid or succinic acid when theconcentration-enhancing polymer is anionic) or, alternatively, enhancingthe rate of dissolution of the composition (e.g., bases such as sodiumacetate or amines when the polymer is anionic). Of course, where thedrug is acid-sensitive, pH modifiers should not be added to thedispersion except as discussed above in connection with includingbuffers or basic excipients within the dispersion.

[1287] Conventional matrix materials, complexing agents, solubilizers,fillers, disintegrating agents (disintegrants), or binders may also beadded as part of the composition itself or added by granulation via wetor mechanical or other means. These materials may comprise up to 90 wt %of the composition.

[1288] Examples of matrix materials, fillers, or diluents includelactose, mannitol, xylitol, microcrystalline cellulose, calciumdiphosphate, dicalcium phosphate and starch.

[1289] Examples of disintegrants include sodium starch glycolate, sodiumalginate, carboxy methyl cellulose sodium, methyl cellulose, andcroscarmellose sodium, and crosslinked forms of polyvinyl pyrrolidonesuch as those sold under the trade name CROSPOVIDONE (available fromBASF Corporation).

[1290] Examples of binders include methyl cellulose, microcrystallinecellulose, starch, and gums such as guar gum, and tragacanth.

[1291] Examples of lubricants include magnesium stearate, calciumstearate, and stearic acid.

[1292] Examples of preservatives include sulfites (an antioxidant),benzalkonium chloride, methyl paraben, propyl paraben, benzyl alcoholand sodium benzoate.

[1293] Examples of suspending agents or thickeners include xanthan gum,starch, guar gum, sodium alginate, carboxymethyl cellulose, sodiumcarboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, polyacrylic acid, silica gel, aluminum silicate, magnesiumsilicate, and titanium dioxide.

[1294] Examples of anticaking agents or fillers include silicon oxideand lactose.

[1295] Examples of solubilizers include ethanol, propylene glycol orpolyethylene glycol.

[1296] Other conventional excipients may be employed in the compositionsof this invention, including those excipients well-known in the art.Generally, excipients such as pigments, lubricants, flavorants, and soforth may be used for customary purposes and in typical amounts withoutadversely affecting the properties of the compositions. These excipientsmay be utilized in order to formulate the composition into tablets,capsules, suspensions, powders for suspension, creams, transdermalpatches, and the like.

[1297] The compositions of the present invention may be delivered by awide variety of routes, including, but not limited to, oral, nasal,rectal, vaginal, subcutaneous, intravenous, and pulmonary. Generally,the oral route is preferred.

[1298] Compositions of this invention may also be used in a wide varietyof dosage forms for administration of drugs. Exemplary dosage forms arepowders or granules that may be taken orally either dry or reconstitutedby addition of water or other liquids to form a paste, slurry,suspension or solution; tablets; capsules; multiparticulates; and pills.Various additives may be mixed, ground, or granulated with thecompositions of this invention to form a material suitable for the abovedosage forms.

[1299] The compositions of the present invention may be formulated invarious forms such that they are delivered as a suspension of particlesin a liquid vehicle. Such suspensions may be formulated as a liquid orpaste at the time of manufacture, or they may be formulated as a drypowder with a liquid, typically water, added at a later time but priorto oral administration. Such powders that are constituted into asuspension are often termed sachets or oral powder for constitution(OPC) formulations. Such dosage forms can be formulated andreconstituted via any known procedure. The simplest approach is toformulate the dosage form as a dry powder that is reconstituted bysimply adding water and agitating. Alternatively, the dosage form may beformulated as a liquid and a dry powder that are combined and agitatedto form the oral suspension. In yet another embodiment, the dosage formcan be formulated as two powders which are reconstituted by first addingwater to one powder to form a solution to which the second powder iscombined with agitation to form the suspension.

[1300] Generally, it is preferred that the dispersion of drug beformulated for long-term storage in the dry state as this promotes thechemical and physical stability of the drug.

[1301] A preferred additive to such formulations is additionalconcentration-enhancing polymer which may act as a thickener orsuspending agent as well as to enhance the concentration of drug in theenvironment of use and may also act to prevent or retard precipitationor crystallization of drug from solution. Such preferred additives arehydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropylmethyl cellulose. In particular, the salts of carboxylic acid functionalpolymers such as cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, and carboxymethyl cellulose are useful inthis regard. Such polymers may be added in their salt forms or the saltform may be formed in situ during reconstitution by adding a base suchas trisodium phosphate and the acid form of such polymers.

[1302] In some cases, the overall dosage form or particles, granules orbeads that make up the dosage form may have superior performance ifcoated with an enteric polymer to prevent or retard dissolution untilthe dosage form leaves the stomach. Exemplary enteric coating materialsinclude hydroxypropyl methyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, celluloseacetate trimellitate, carboxylic acid-functionalized polymethacrylates,and carboxylic acid-functionalized polyacrylate.

[1303] Compositions of this invention may be administered in acontrolled release dosage form. In one such dosage form, the compositionof the drug and polymer is incorporated into an erodible polymericmatrix device. By an erodible matrix is meant aqueous-erodible orwater-swellable or aqueous-soluble in the sense of being either erodibleor swellable or dissolvable in pure water or requiring the presence ofan acid or base to ionize the polymeric matrix sufficiently to causeerosion or dissolution. When contacted with the aqueous environment ofuse, the erodible polymeric matrix imbibes water and forms anaqueous-swollen gel or “matrix” that entraps the dispersion of drug andpolymer. The aqueous-swollen matrix gradually erodes, swells,disintegrates or dissolves in the environment of use, therebycontrolling the release of the dispersion to the environment of use.Examples of such dosage forms are disclosed more fully in commonlyassigned pending U.S. patent application Ser. No. 09/495,059 filed Jan.31, 2000 which claimed the benefit of priority of provisional patentapplication Serial No. 60/119,400 filed Feb. 10, 1999, the relevantdisclosure of which is herein incorporated by reference.

[1304] Alternatively, the compositions of the present invention may beadministered by or incorporated into a non-erodible matrix device.

[1305] Alternatively, the compositions of the invention may be deliveredusing a coated osmotic controlled release dosage form. This dosage formhas two components: (a) the core which contains an osmotic agent and thedispersion of drug and concentration-enhancing polymer; and (b) anon-dissolving and non-eroding coating surrounding the core, the coatingcontrolling the influx of water to the core from an aqueous environmentof use so as to cause drug release by extrusion of some or all of thecore to the environment of use. The osmotic agent contained in the coreof this device may be an aqueous-swellable hydrophilic polymer, osmogen,or osmagent. The coating is preferably polymeric, aqueous-permeable, andhas at least one delivery port. Examples of such dosage forms aredisclosed more fully in commonly assigned pending U.S. patentapplication Ser. No. 09/495,061 filed Jan. 31, 2000 which claimed thebenefit of priority of provisional Patent Application Serial No.60/119,406 filed Feb. 10, 1999, the relevant disclosure of which isherein incorporated by reference.

[1306] Alternatively, the compositions may be delivered via a coatedhydrogel controlled release form having at least two components: (a) acore comprising the dispersion of the present invention and a hydrogel,and (b) a coating through which the dispersion has passage when thedosage form is exposed to a use environment. Examples of such dosageforms are more fully disclosed in commonly assigned European PatentEP0378404, the relevant disclosure of which is herein incorporated byreference.

[1307] Alternatively, the drug mixture of the invention may be deliveredvia a coated hydrogel controlled release dosage form having at leastthree components: (a) a composition containing the dispersion, (b) awater-swellable composition wherein the water-swellable composition isin a separate region within a core formed by the drug-containingcomposition and the water-swellable composition, and (c) a coatingaround the core that is water-permeable, water-insoluble, and has atleast one delivery port therethrough. In use, the core imbibes waterthrough the coating, swelling the water-swellable composition andincreasing the pressure within the core, and fluidizing thedispersion-containing composition. Because the coating remains intact,the dispersion-containing composition is extruded out of the deliveryport into an environment of use. Examples of such dosage forms are morefully disclosed in commonly assigned pending U.S. patent applicationSer. No. 09/745,095 filed Dec. 20, 2000, which claimed the benefit ofpriority of provisional patent application 60/171,968 filed Dec. 23,1999, the relevant disclosure of which is herein incorporated byreference.

[1308] Alternatively, the compositions may be administered asmultiparticulates. Multiparticulates generally refer to dosage formsthat comprise a multiplicity of particles that may range in size fromabout 10 □m to about 2 mm, more typically about 100 □m to 1 mm indiameter. Such multiparticulates may be packaged, for example, in acapsule such as a gelatin capsule or a capsule formed from anaqueous-soluble polymer such as HPMCAS, HPMC or starch or they may bedosed as a suspension or slurry in a liquid.

[1309] Such multiparticulates may be made by any known process, such aswet- and dry-granulation processes, extrusion/spheronization,roller-compaction, melt-congealing processes or by spray-coating seedcores. For example, in wet- and dry-granulation processes, thecomposition of drug and concentration-enhancing polymer is prepared asdescribed above. This composition is then granulated to formmultiparticulates of the desired size. Other excipients, such as abinder (e.g., microcrystalline cellulose), may be blended with thecomposition to aid in processing and forming the multiparticulates. Inthe case of wet granulation, a binder such as microcrystalline cellulosemay be included in the granulation fluid to aid in forming a suitablemultiparticulate.

[1310] In any case, the resulting particles may themselves constitutethe multiparticulate dosage form or they may be coated by variousfilm-forming materials such as enteric polymers or water-swellable orwater-soluble polymers, or they may be combined with other excipients orvehicles to aid in dosing to patients.

[1311] Compositions of the present invention may be used to treat anycondition which is subject to treatment by administering a drug.

[1312] Other features and embodiments of the invention will becomeapparent from the following examples which are given for illustration ofthe invention rather than for limiting its intended scope.

EXAMPLES Examples 1-2

[1313] This example discloses solid amorphous dispersions of anacid-sensitive, low-solubility drug and neutral polymer. For Example 1,a dispersion of quinoxaline-2-carboxylic acid[4(R)-carbamoyl-1(S)-3-fluorobenzyl)-2(S),7-dihydroxy-7-methyl-octyl]amide (Drug 1) and the neutral polymer hydroxypropyl methyl cellulose(HPMC E3 Prem) was made by preparing a solution containing 0.125 wt %Drug 1 and 0.375 wt % HPMC in methanol, and spraying the solution into adrying chamber using an atomizing spray nozzle as described below. ForExample 2, a dispersion of Drug 1 with the neutral polymer polyvinylpyrollidone (PVP-Plasdone K-29/32 available from ISP Technologies Inc.,Wayne, N.J.) was made by preparing a solution containing 0.33 wt % Drug1 and 1.0 wt % PVP in acetone/methanol (9/1, wt/wt), and spray-dryingthe solution as described below.

[1314] For Control C1, a dispersion of Drug 1 with hydroxy propyl methylcellulose acetate succinate, LF-grade (HPMCAS-LF) (with about 14-18 wt %or 350-450 meq of succinate groups per mol of polymer) was made bypreparing a solution containing 0.33 wt % Drug 1 and 1.0 wt % HPMCAS-LFin acetone, and spray-drying the solution as described below.

[1315] For Examples 1 and 2, and Control C1, the solutions werespray-dried by pumping the solution into a “mini” spray-dryer apparatusvia a Cole Parmer 74900 series rate-controlling syringe pump at a rateof 1.3 mL/min. The drug/polymer solution was atomized through a SprayingSystems Co. two-fluid nozzle, Model No. SU1A using a heated stream ofnitrogen (100 □C). The spray solution was sprayed into an 11-cm diameterstainless steel chamber. The resulting solid amorphous dispersionscontaining 25 wt % Drug 1 were collected on filter paper, dried undervacuum, and stored in a dessicator. Table 1 summarizes the spray-dryingvariables. TABLE 1 Drug Polymer Solvent Mass Drug Mass Mass Solvent Ex.(mg) No. (mg) Polymer (g) (wt/wt) 1 50 1 150 HPMC 40 Methanol 2 50 1 150PVP 15 Acetone/ methanol (9/1) C1 50 1 150 HPMCAS 15 Acetone

Example 3

[1316] In this example the chemical stability of the dispersions ofExamples 1 and 2 was assessed by monitoring the potency of the drugbefore and after exposure to increased temperatures and relativehumidity (RH) in accelerated-aging studies. Dispersions of Examples 1and 2, and Control C1, were placed in two controlled atmospherechambers: one chamber maintained at 70° C. (no RH control); the secondchamber maintained at 40° C. and 75% RH. Potencies of the dispersionsbefore and after storage were determined using HPLC. A Kromasil C₄HPLCcolumn was used with a mobile phase of 45 vol % of 0.2 vol % H₃PO₄, and55 vol % acetonitrile. UV detection was measured at 245 nm. Drug 1potency was the percent of the total HPLC peak area corresponding to thetheoretical amount of drug originally present in the dispersion prior tostorage based on the amount of drug present in the initial solutionsbefore spray-drying. The results are shown in Table 2 below. TABLE 2Degree of Drug 1 Degree of Degrad- Conc. Pot. Degrad- Pot. ation in thePot. Day 4 ation Day 14 Day 14 Aqueous Disper- Before at Day 4 at 40°C./ at 40° C./ Soluble sion Storage 70° C. at 70° C. 75% RH 75% RH Ex.Polymer (wt %) (wt %) (wt %) (wt %) (wt %) (wt %) 1 HPMC 25 100 100 <1100 <1 2 PVP 25 100 100 <1 99 1 C1 HPMCAS- 25 94 <1 >93 <1 >93 LF

[1317] As the data show, the dispersions of Examples 1 and 2 formed withneutral polymers were much more chemically stable than the controldispersion C1 formed from HPMCAS. In fact, the dispersions of bothExample 1 and Example 2 had a relative degree of improvement whencompared with the control C1 of greater than 93 after only two weeks at40° C./75% RH.

Example 4

[1318] In this example the dispersions of Examples 1 and 2 were testedto show that the dispersions provided concentration-enhancement of thedrug in aqueous solution. For Control C2, the crystalline form of thedrug alone was used without further processing. For this test, 7.2 mg ofthe dispersions of Examples 1 and 2, and 3.6 mg of Control C2, was addedto respective microcentrifuge tubes. The tubes were placed in a 37° C.temperature-controlled bath, and 1.8 mL phosphate buffered saline (PBS)at pH 6.5 and 290 mOsm/kg was added to each. The samples were quicklymixed using a vortex mixer for about 60 seconds. The samples werecentrifuged at 13,000 G at 37° C. for 1 minute. The resultingsupernatant solutions were then sampled and diluted 1:6 (by volume) withmethanol and then analyzed by high-performance liquid chromatography(HPLC). The contents of the tubes were mixed on the vortex mixer andallowed to stand undisturbed at 37° C. until the next sample was taken.Samples were collected at 4, 10, 20, 40, 90, and 1200 minutes. Theresults are shown in Table 3. TABLE 3 Time [Drug 1] AUC Example (min)(μg/mL) (min*μg/mL) 1 0 0 0 4 863 1,700 10 895 7,000 20 885 15,900 40925 34,000 90 907 79,800 1200 926 1,097,100 2 0 0 0 4 923 1,800 10 9287,400 20 913 16,600 40 947 35,200 90 927 82,100 1200 929 1,112,100 C2  00 0 4 274 600 10 266 2,200 20 338 5,200 40 289 11,500 90 300 26,200 1200303 360,800

[1319] The concentrations of Drug 1 obtained in these samples were usedto determine the values of the maximum drug concentration between 0 and90 minutes (C_(max90)) and the area under the curve from 0 to 90 minutes(AUC₉₀). The results are shown in Table 4. TABLE 4 C_(max90) Example(μg/mL) AUC₉₀ (min*μg/mL) 1 925 79,800 2 947 82,000 C2  338 26,200

[1320] As can be seen from the data, the neutral polymers HPMC and PVPare both concentration-enhancing polymers in the dispersions of Examples1 and 2. The Drug 1 and HPMC dispersion of Example 1 provided aC_(max90) that was 2.7-fold, and an AUC₉₀ that was 3.0-fold, that of thecontrol C2, while the PVP Drug 1 dispersion of Example 2 provided aC_(max90) that was 2.8-fold, and an AUC₉₀ that was 3.1-fold, that ofControl C2.

Example 5

[1321] The dispersion of Example 2 was stored for 1.5 years at roomtemperature (sealed), and then analyzed for Drug 1 potency by HPLC usingthe method described in Example 3. Results are shown in Table 5. TABLE 5Drug 1 Potency After Conc. Potency 1.5 yrs in the Before at roomDispersion Storage temp./sealed Ex. Polymer (wt %) (wt %) (wt %) 2 PVP25 100 100

[1322] As the data show, the dispersion of Example 2 formed with PVP ischemically stable for extended duration under ambient conditions. Thisdata is consistent with the results of accelerated storage stabilitytests for the dispersion of Example 2 (stored at 70° C. and 40° C./75%RH) shown in Example 3 (Table 2).

[1323] In vitro dissolution tests were performed for the dispersion ofExample 2 before and after 1.5 years storage, using the proceduredescribed in Example 4, with the following exceptions: 7.2 mg of thedispersion of Example 2 was used in initial dissolution tests, and 5.4mg of Example 2 was used in dissolution tests after 1.5 years storage.The results are reported as a percentage of the total dose dissolved, tofacilitate comparison. The results are shown in Table 6. TABLE 6 Drug 1Concentration Initial Drug 1 After 1.5 yrs Time Concentration Storage(min) (% dissolved) (% dissolved) 0  0  0 4 91 95 10 92 90 20 90 87 4094 88 90 92 98 1200 92 89

[1324] As can be seen from the data, the dissolution performance of thedispersion of Example 2 was maintained after 1.5 years storage,indicating that the dispersion is physically stable and Drug 1 ischemically stable for at least 1.5 years at ambient conditions.

Examples 6-9

[1325] These examples disclose additional dispersions of Drug 1 preparedwith the dispersion polymers HPMC, Eudragit® E100 (available from RohmAmerica Inc., Piscataway, N.J.), and an HPMC/Eudragit® E100 mixture.Eudragit E100 is a polymethacrylate polymer which contains basic groups.Examples 6 through 9 were prepared by spray-drying a solution of Drug 1and polymer, as described in Example 1. For Example 6, the solutionconsisted of 1.25 wt % Drug 1 and 3.75 wt % HPMC in methanol/water (9/1,wt/wt). For Example 7, the solution consisted of 0.25 wt % Drug 1 and4.75 wt % HPMC in methanol/water (9/1, wt/wt). For Example 8, thesolution consisted of 1.25 wt % Drug 1 and 3.75 wt % Eudragit® E100 inmethanol/acetone (1/1, wt/wt). For Example 9, the solution consisted of1.25 wt % Drug 1 and 3.75 wt % HPMC/Eudragit (1/1 wt/wt) inmethanol/water (9/1, wt/wt). The solution variables are summarized inTable 7.

[1326] For Control C3, the solution consisted of 1.25 wt % Drug 1 and3.75 wt % HPMCAS-HF (HF grade) and methanol. TABLE 7 Drug PolymerSolvent Mass Drug Mass Mass Solvent Ex. (mg) No. (mg) Polymer (g)(wt/wt) 6 50 1 150 HPMC 4 methanol/ water (9/1) 7 50 1 950 HPMC 30methanol/ water (9/1) 8 125 1 375 Eudragit 10 acetone/ methanol (1/1) 9250 1 375/375 HPMC/ 20 methanol/ Eudragit water (9/1) C3 50 1 150HPMCAS- 4 methanol HF

Example 10

[1327] In this example the chemical stability of the dispersions ofExamples 6-9 was assessed. Dispersions were stored under elevatedtemperature and humidity conditions to increase the rate of physicalchanges occurring in the materials in order to simulate a longer storageinterval in a typical storage environment. Drug purity was determinedusing HPLC as in Example 3. Results of purity analysis of thedispersions of Drug 1 after various storage intervals under variousstorage conditions are shown in Table 8. TABLE 8 Potency Day Degree ofAqueous- Drug 1 Conc. in 5 at Degradation Soluble the Dispersion 40° C./Day 5 Ex. Polymer (wt %) 75 RH (wt %) (wt %) 6 HPMC 25 97.3 2.7 7 HPMC 596.3 3.7 8 Eudragit 25 95.6 4.4 9 HPMC/ 25 97.9 2.1 Eudragit C3 HPMCAS-HF 25 60 40

[1328] The chemical stability of the acid-sensitive drug in dispersionsof Examples 6-9 containing neutral polymers were all significantlyimproved in comparison to the stability of dispersions of the control C3having the acidic polymer HPMCAS-HF. The relative degree of improvementcompared with the control C3 was 14.8 for Example 6, 10.8 for Example 7,9.1 for Example 8, and 19.0 for Example 9.

Examples 11-12

[1329] These examples disclose dispersions of Drug 1 in a neutralpolymer with added buffer. Examples 11 and 12 were prepared with Drug 1,as described in Example 1, with the following exceptions: for Example11, the solution to be spray-dried consisted of 1.25 wt % Drug 1, 0.513wt % sodium acetate, and 3.75 wt % HPMC in methanol/water (9/1); and forExample 12, the solution consisted of 1.25 wt % Drug 1, 0.32 wt % sodiumbicarbonate, and 3.75 wt % HPMC in methanol/water (9/1). The solutionvariables are summarized in Table 9. TABLE 9 Excip- Poly- Drug ient merMass Excip- Mass Mass Solvent Solvent Ex. (mg) ient (mg) Polymer (mg)(wt/wt) Mass (g) 11 125 NaOAc 51.4 HPMC 375 MeOH/ 10 water (9/1) 12 125NaHCO₃ 32 HPMC 375 MeOH/ 10 water (9/1)

Example 13

[1330] Chemical stability of the acid-sensitive Drug 1 in thedispersions of Examples 11 and 12 containing buffers was determined bymeasuring the drug purity before and after storage for Examples 11 and12, and Control C3. Dispersions were stored under elevated temperatureand humidity conditions to increase the rate of changes occurring in thematerials in order to simulate a longer storage interval in a typicalstorage environment. Drug purity was determined using HPLC. Results ofanalysis of dispersions of Examples 11 and 12 after five days at 40°C./75% RH are shown in Table 10. TABLE 10 Drug 1 Conc. Potency in theDay 5 at Degree of Aqueous-Soluble Dispersion 40° C./75% RH DegradationEx. Polymer/Buffer (wt %) (%) (%) 11 HPMC/NaOAc 23 97.79 2.2 12HPMC/NaHCO₃ 24 95.65 4.3 C3 HPMCAS-HF 25 60 40

[1331] The stability of the dispersions with neutral polymers containingbuffers was significantly improved in comparison to the stability of thedispersion with HPMCAS-HF. The relative degree of improvement after fivedays compared with the Control C3 was 18.2 for Example 11, and 9.3 forExample 12.

Example 14

[1332] This example discloses dispersions of a second acid-sensitivedrug, quinoxaline-2-carboxylic acid[1-benzyl-4-(4,4-difluoro-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide(Drug 2). For Example 14, a dispersion of Drug 2 and PVP was made byfirst preparing a solution containing 0.030 wt % drug and 0.27 wt % PVPin methanol/acetone (1/9 wt/wt), and then spraying the solution into adrying chamber using an atomizing spray nozzle in the manner describedin Example 1.

[1333] For Control C4, a dispersion of Drug 2 and HPMCAS-LF was made bypreparing a solution containing 0.030 wt % Drug 2 and 0.27 wt %HPMCAS-LF in acetone, and spray-drying as described above. For ControlC5, a dispersion of Drug 2 with the acidic polymer hydroxypropyl methylcellulose phthalate (HPMCP) was made by preparing a solution containing0.030 wt % drug and 0.27 wt % HPMCP in acetone, and spray-drying asdescribed above. Table 11 summarizes the solution variables. TABLE 11Drug Polymer Solvent Mass Drug Mass Mass Solvent Ex. (mg) No. (mg)Polymer (g) (wt/wt) 14 3 12 27 PVP 10 methanol/ acetone (1/9) C4 3 2 27HPMCAS 10 acetone C5 3 2 27 HPMCP 10 acetone

Example 15

[1334] This example assesses the stability of the dispersion of Example14. The dispersions of Example 14 and Controls C4 and C5 were stored incontrolled atmosphere chambers for 7 days at room temperature and 0% RH.Potencies of the dispersions before and after storage were determinedusing HPLC as in Example 3, with the following exceptions. An HP ODSHypersil column was used with a mobile phase of 60 vol % 0.02M KH₂PO₄(pH3.0) and 40 vol % acetonitrile. UV detection was measured at 248 nm. Theresults are shown in Table 12 below. TABLE 12 Drug 2 Conc. Potency Day 7Aqueous- In the at room Degree of Soluble Dispersion temp/0% RHDegradation Ex. Polymer (wt %) (wt %) (wt %) 14 PVP 10 84 16 C4HPMCAS-LF 10 45 55 C5 HPMCP 10 53 47

[1335] As the data show, the dispersion of Example 14 comprised of theacid-sensitive drug and neutral polymer PVP had improved chemicalstability relative dispersions formed using either of the acidicpolymers HPMCAS-LF or HPMCP. Example 14 had a relative degree ofimprovement when compared with control C4 of 3.4, and a relative degreeof improvement when compared with control C5 of 2.9.

Example 16

[1336] This example measures the concentration-enhancing properties ofthe PVP dispersion of 14. Dissolution tests were performed, as describedin Example 4 with following exceptions: the PBS solution contained 7.3mM sodium taurocholic acid and 1.4 mM 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine (model fasted duodenal(MFD) solution). 1.8 mg of dispersion was added to 1.8 mL of test media.For Control C6, 0.18 mg of the crystalline form of the Drug 2 alone wasused without further processing and added to 1.8 mL of solution. Theresults are shown in Table 13 below. TABLE 13 Time Drug 2 AUC Example(min) (μg/mL) (min*□g/mL) 14 0 0 0 4 57 100 10 55 500 20 55 1,000 40 522,100 90 54 4,700 C6 0 0 0 4 2 0 10 4 0 20 4 100 40 4 100 90 7 400

[1337] The concentrations of Drug 2 obtained in these samples were usedto determine the values of C_(max90) and AUC₉₀. The results are shown inTable 14. As can be seen from the data, dispersions of Example 14provided an 8-fold improvement in C_(max90) and a 12-fold improvement inAUC₉₀. TABLE 14 C_(max90) AUC₉₀ Example (μg/mL) (min*μg/mL) 14 57 4700C6  7  400

Examples 17-18

[1338] These examples disclose dispersions of a third acid-sensitivedrug, quinoxaline-2-carboxylic acid [1-benzyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide(Drug 3). For Example 17, a dispersion of Drug 3 and HPMC was made bypreparing a solution containing 0.050 wt % Drug 3 and 0.45 wt % HPMC inmethanol, and spraying the solution into a drying chamber using anatomizing spray nozzle, as described in Example 1. For Example 18, adispersion of Drug 3 with PVP was made by preparing a solutioncontaining 0.030 wt % Drug 3 and 0.27 wt % PVP in methanol/acetone (1/9wt/wt), and spray-drying as described above.

[1339] For Control C7, a dispersion of Drug 3 and HPMCAS-LF was made bypreparing a solution containing 0.030 wt % drug and 0.27 wt % HPMCAS-LFin acetone, and spray-drying as described above. For Control C8, adispersion of Drug 3 and HPMCP was made by preparing a solutioncontaining 0.030 wt % drug and 0.27 wt % HPMCP in acetone, andspray-drying as described above. Table 15 summarizes the spray-dryingvariables. TABLE 15 Drug Polymer Solvent Mass Drug Mass Mass Solvent Ex.(mg) No. (mg) Polymer (g) (wt/wt) 17 5 3 45 HPMC 10 methanol 18 3 3 27PVP 10 acetone/ methanol (9/1) C7 3 3 27 HPMCAS-LF 10 acetone C8 3 3 27HPMCP 10 acetone

Example 19

[1340] This example demonstrates the relative chemical stability of thedispersions of Examples 17 and 18. The dispersions of Examples 17 and18, and Controls C7 and C8, were placed in controlled atmospherechambers for 6 days at room temperature and 0% RH (the HPMC dispersionof Example 16 was stored for 4 days). Potencies of the dispersionsbefore and after storage were determined using HPLC, using the methoddescribed in Example 15 above. The results are shown in Table 16 below.TABLE 16 Drug 3 Conc. Aqueous- in the Potency Day 6 at Degree of SolubleDispersion room temp/0% RH Degradation Ex. Polymer (wt %) (wt %) (wt %)17 HPMC 10 92 (4 days) 8 18 PVP 10 95 5 C7 HPMCAS-LF 10 46 54 C8 HPMCP10 56 44

[1341] The data show that dispersions of the acid-sensitive drug andneutral polymers were more stable than dispersions formed with theacidic polymers HPMCAS-LF and HPMCP. The dispersion of Example 18 had arelative degree of improvement of 10.8 when compared with the controlC7, and 8.8 when compared with the control C8.

Example 20

[1342] This example demonstrates the concentration enhancement providedby the dispersion of Example 18. Dissolution tests were performed, asdescribed in Example 4 with the following exceptions: samples weretested in MFD Solution, and 1.8 mg of dispersion was added to 1.8 mLs ofMFD Solution. Control C9 was simply 0.18 mg of the crystalline Drug 3alone add to 1.8 mL of MFD solution. The results are shown in Table 17below. TABLE 17 Time Drug 3 AUC Example (min) (μg/mL) (min*□g/mL) 17 0 00 4 88 200 10 83 700 20 80 1,500 40 79 3,100 90 77 7,000 C9 0 0 0 4 4 010 6 0 20 8 100 40 11 300 90 13 900

[1343] The concentrations of Drug 3 obtained in these samples were usedto determine the values of C_(max90) and AUC₉₀. The results are shown inTable 18. TABLE 18 C_(max90) AUC₉₀ Example (μg/mL) (min*μg/mL) 18 887100 C9 13  900

[1344] As can be seen from the data, dispersions of Drug 3, anacid-sensitive drug, and the neutral polymer, PVP, providedconcentration-enhancement in an aqueous environment of use. Thedispersion of Example 18 provided a C_(max90) that was 6.8-fold, and anAUC₉₀ that was 7.9-fold that of the control C9.

Examples 21-29

[1345] These examples disclose dispersions formed from variouslow-solubility drugs and neutral amphiphilic, hydroxyl-functional vinylcopolymers, particularly vinyl acetate/vinyl alcohol copolymers(hereinafter “VAVAC”). For Examples 21 to 24, the dispersions were madeusing Drug 1. For Examples 25 to 27, the dispersions were made using5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-3-((3R,4S)-dihydroxypyrrolidin-1-yl)-(2R)-hydroxy-3-oxypropyl]amide (“Drug 4”).For Examples 28 to 29, the dispersions were made using(+)-N-{3-[3-(4-fluorophenoxy)phenyl]-2-cyclopenten-1-yl}-N-hydroxyurea(“Drug 5”).

[1346] Several different grades of VAVAC were used. For Examples 23, 25and 28, the VAVAC, referred to herein as “VAVAC-20%,” was 80% hydrolyzed(meaning that about 20% of the vinyl repeat units were acetylated), andhad an average molecular weight of 9,000-10,000 daltons. The VAVAC-20%was supplied by Aldrich Chemical Company of lot #36,062-7.

[1347] For Examples 21, 26 and 29, the VAVAC, referred to herein as“VAVAC-12%,” was approximately 88% hydrolyzed (approximately 11-13% ofthe repeat units were acetylated), and had an average molecular weightof 13,000-23,000 daltons. VAVAC-12% was supplied by Aldrich ChemicalCompany, lot #36,317-0.

[1348] For Examples 22, 24 and 27, the VAVAC, referred to herein as“VAVAC-2%,” was 98% hydrolyzed (approximately 2% of the repeat unitswere acetylated) and had an average molecular weight of 13,000-23,000daltons. VAVAC-2% was supplied by Aldrich Chemical Company, lot#34,840-6.

[1349] To form the dispersions of Examples 21-29, solutions containingdrug and polymer in a solvent were spray-dried by pumping each solutioninto a “mini” spray-drier apparatus as described in Example 1.

[1350] Table 19 summarizes the variables for the solutions of Examples21-29. TABLE 19 Poly- Sol- Drug Drug mer Spray vent Mass Conc.* MassSolvent Mass Ex. Drug (mg) (%) Polymer (mg) wt/wt (g) 21 1 62 25 VAVAC-186 MeOH/H2O 18 12% (4/1) 22 1 692 75 VAVAC-2% 231 MeOH/H2O 50 (1/1) 231 664 50 VAVAC- 664 MeOH/H2O 105 20% (4/1) 24 1 522 25 VAVAC-2% 1565MeOH/H2O 110 (4/1) 25 4 110 25 VAVAC- 330 MeOH/H2O 33.8 20% (4/1) 26 4126 25 VAVAC- 376 MeOH/H2O 50 12% (1.8/1) 27 4 78 25 VAVAC-2% 233MeOH/H2O 20.6 (1/1) 28 5 37 10 VAVAC- 330 MeOH/H2O 33.8 20% (4/1) 29 542 10 VAVAC- 376 MeOH/H2O 50 12% (1.8/1)

Example 30

[1351] In this example the chemical stability of the dispersions ofExamples 23 and 24 was assessed. The dispersions were stored for threeweeks at 40° C. and 75% RH, then analyzed for Drug 1 potency by HPLCusing the method described in Example 3. Results are shown in Table 20,as are the results for Control C1, a dispersion of Drug 1 and the acidicpolymer HPMCAS-LF (prepared in Example 1). TABLE 20 Drug 1 Conc. Potencyin the Pot. After 3 Degree of Relative Disper- Before weeks @ Degrad-Degree of sion Storage 40° C./75 RH ation @3 Improve- Ex. Polymer (wt %)(%) (%) wks (wt %) ment 23 VAVAC- 50 98 97 3 >33 20% 24 VAVAC- 25 98 964 >25 2% C1 HPMCAS- 25 94  <1*   >99*   — LF

[1352] As the data show, the dispersions of Examples 23 and 24 formedwith VAVAC have improved chemical stability when compared with ControlC1, showing a relative degree of improvement of >33 for Example 23and >25 for Example 24.

Example 31

[1353] In vitro dissolution tests were performed for Examples 21-24,using the procedure described in Example 4, with the followingexceptions: 14.4 mg of the dispersions of Example 21, 4.8 mg of thedispersion Example 22, 7.2 mg of the dispersion of Example 23, and 14.4mg of the dispersion of Example 24 were added to respective tubes. 1.8mL of PBS was added to each tube to achieve a theoretical total Drug 1concentration of approximately 2000 μg/mL if all of the drug were todissolve completely. For comparison, a Control C10 of 1.8 mg ofcrystalline Drug 1 was added to 1.8 mL of PBS. The results are shown inTable 21. TABLE 21 Drug 1 Time Concentration AUC Example (min) (μg/mL)(min*μg/mL) 21 0 0 0 4 1554 3,100 10 1860 13,300 20 1474 30,000 40 74452,200 90 685 87,900 180 632 147,200 1200 580 790,000 22 0 0 0 4 8091,600 10 1019 7,100 20 1162 18,000 40 1211 41,700 90 1273 103,835 12001117 1,430,292 23 0 0 0 4 1698 3,400 10 1685 13,500 20 1076 27,400 40608 44,200 90 552 73,200 1200 499 656,500 24 0 0 0 4 1081 2,200 10 12799,200 20 1334 22,300 40 1342 49,100 90 662 99,200 1200 478 731,900 C10 00 0 4 241 500 10 256 2,000 20 299 4,700 40 260 10,300 90 295 25,500 180298 49,400 1200 313 361,000

[1354] The concentrations of Drug 1 obtained in these samples were usedto determine the values of C_(max90) and AUC₉₀. The results are shownbelow in Table 22. TABLE 22 C_(max90) AUC₉₀ Example (μg/mL) (min*μg/mL)21 1860 87,900 22 1273 103,800  23 1698 73,200 24 1342 99,200 C10   29925,500

[1355] As can be seen from the data, the dispersions of Examples 21-24provided concentration-enhancement over that of Control C10 (crystallineDrug 1 alone). Example 21 provided a C_(max90) that was 6.2-fold and anAUC₉₀ that was 3.4-fold that of Control C10; Example 22 provided aC_(max90) that was 4.3-fold, and an AUC₉₀ that was 4.1-fold that of theControl C10; Example 23 provided a C_(max90) that was 5.7-fold and anAUC₉₀ that was 2.9-fold that of Control C10; and Example 24 provided aC_(max90) that was 4.5-fold and an AUC₉₀ that was 3.9-fold that ofControl C10

Example 32

[1356] This example demonstrates a composition comprising a dispersionof an acid-sensitive drug and a neutral polymer mixed with an acidicconcentration-enhancing polymer, namely HPMCAS-HF. Example 32 wasprepared by mixing the dispersion of Example 21 with HPMCAS-HF. An invitro dissolution test was performed using the procedure described inExample 4, with the following exceptions: 14.4 mg of the dispersion ofExample 21 and 14.4 mg of HPMCAS-HF were added to 1.8 mL of PBS solutionfor a total theoretical Drug 1 concentration of approximately 2000 μg/mLif all of the drug were to dissolve completely. The results are shown inTable 23. TABLE 23 Drug 1 Time Concentration AUC Example (min) (μg/mL)(min*μg/mL) 32 0 0 0 4 1365 2,700 10 1441 11,100 20 1399 25,300 40 157755,100 90 1541 133,100 180 1648 276,600 1200 1863 2,021,700

[1357] The concentrations of Drug 1 obtained in these samples were usedto determine the values of C_(max90) and AUC₉₀. The results are shownbelow in Table 24. TABLE 24 C_(max90) AUC₉₀ Example (μg/mL) (min*μg/mL)32 1577 133,100 21 1860  87,900

[1358] As can be seen from the data, the composition of Example 32(i.e., the dispersion of Example 21 and HPMCAS) had an improved AUC₉₀relative to the dispersion of Example 21 alone. Results of dissolutiontests for Example 21 were shown previously in Table 22, however, theyare shown again in Table 24 for comparison

Example 33

[1359] In vitro dissolution tests were performed for Examples 25-27using the procedure described in Example 4, with the followingexceptions: 14.4 mg each of the dispersions of Examples 25-27 were addedto separate, respective centrifuge tubes. 1.8 mL PBS was added to eachtube. For comparison, Control C11 was prepared consisting of 3.6 mg ofcrystalline Drug 4 added to 1.8 mL PBS. Drug 4 concentration in thesamples was determined using HPLC. A Zorbax SB C₁₈ HPLC column was usedwith a mobile phase of 35 vol. % water and 65 vol. % methanol. UVdetection was measured at 297 nm. The results are shown in Table 25.TABLE 25 Time [Drug 4] AUC Example (min) (μg/mL) (min*μg/mL) 25 0 0 0 41580 3,200 10 1581 12,600 20 1570 28,400 40 1594 60,000 90 1476 136,0001200 248 1,093,600 26 0 0 0 4 1957 3,900 10 1993 15,800 20 1948 35,50040 1980 74,700 90 1959 173,200 1200 163 1,350,900 27 0 0 0 4 735 1,50010 733 5,900 20 707 13,100 40 691 27,100 90 676 61,200 1200 147 518,000C11  0 0 0 4 131 300 10 114 1,000 20 124 2,200 40 107 4,500 90 12610,300 1200 72 120,200

[1360] The concentrations of Drug 4 obtained in these samples were usedto determine the values of C_(max90) and AUC₉₀. The results are shownbelow in Table 26. TABLE 26 C_(max90) AUC₉₀ Example (μg/mL) (min*μg/mL)25 1594 136,800 26 1993 173,200 27 735 61,200 C11  131 10,300

[1361] As can be seen from the data, the dispersions of Examples 25-27provided concentration-enhancement over that of Control C11, thecrystalline Drug 4 alone. The dispersion of Example 25 provided aC_(max90) that was 12-fold and an AUC₉₀ that was 13-fold that of ControlC11; Example 26 provided a C_(max90) that was 15-fold and an AUC₉₀ thatwas 17-fold that provided by Control C11; and Example 27 provided aC_(max90) that was 6-fold, and an AUC₉₀ that was 6-fold that of ControlC11.

Example 34

[1362] In vitro dissolution tests were performed for Examples 28-29,using the procedure described in Example 4, with the followingexceptions: 9 mg each of the dispersions of Examples 28-29 were added toseparate respective centrifuge tubes. 1.8 mL of MFD solution was thenadded to each tube. For comparison, Control C12 was prepared consistingof 0.36 mg of crystalline Drug 5 added to 1.8 mL of MFD solution for atotal theoretical concentration of 200 μg/mL if all of the drugdissolved. Drug 5 concentration in the samples was determined usingHPLC. A Waters Symmetry C₁₈HPLC column was used with a mobile phase of50 vol. % (0.3 vol. % glacial acetic acid, 0.2 vol. % TEA in water) and50 vol. % acetonitrile. UV detection was measured at 260 nm. The resultsare shown in Table 27. TABLE 27 Drug 5 Time Concentration AUC Example(min) (μg/mL) (min*μg/mL) 28 0 0 0 4 211 400 10 180 1,600 20 168 3,30040 155 6,600 90 144 14,000 1200 139 171,100 29 0 0 0 4 210 400 10 1921,600 20 186 3,500 40 175 7,100 90 169 15,700 1200 155 195,500 C12  0 00 4 9 0 10 15 100 20 21 300 40 27 800 90 32 2,200 1200 42 43,300

[1363] The concentrations of Drug 5 obtained in these samples were usedto determine the values of C_(max90) and AUC₉₀. The results are shownbelow in Table 28. While the amount of Drug 5 used in the Control C12was less than the amount of Drug 5 in the last compositions of Examples28 and 29, nevertheless a sufficient amount of Drug 5 in excess of thesolubility of Drug 5 was used in Control C12 in order to provide anaccurate measure of the performance of Examples 28 and 29 relative tocrystalline drug. TABLE 28 C_(max90) AUC₉₀ Example (μg/mL) (min*μg/mL)28 211 14,000 29 210 15,700 C12   32  2,200

[1364] As can be seen from the data, the dispersions of Examples 28-29provided concentration-enhancement over that of crystalline Drug 5alone. Example 28 provided a C_(max90) that was 6.6-fold and an AUC₉₀that was 6.4-fold that of Control C12; and Example 29 provided aC_(max90) that was 6.6-fold and an AUC₉₀ that was 7.1-fold that providedby Control C12.

Examples 35-38

[1365] Examples 35 and 36 were dispersions of Drug 4 prepared with thedispersion polymers PVP and HPMC respectively. For Examples 37 and 38,dispersions of Drug 5 and the polymers PVP and HPMC were prepared. Toform the dispersions of Examples 35-38, solutions containing drug andpolymer in a solvent were spray-dried by pumping each solution into a“mini” spray-drier apparatus as described in Example 1. Table 29summaries the variables for the solutions used to prepare Examples35-38. TABLE 29 Drug Drug Polymer Spray Solvent Mass Conc.* Mass SolventMass Ex. Drug (mg) (%) Polymer (mg) (wt/wt) (g) 35 4 50 25 PVP 150acetone 15 36 4 50 25 HPMC 150 MeOH/ 15 water (9/1) 37 5 50 10 PVP 450Acetone 80 38 5 50 10 HPMC 450 MeOH/ 80 acetone (1/1)

Example 39

[1366] In vitro dissolution tests were performed for Examples 35-38,using the procedures described in Example 4, with the followingexceptions: 14.4 mg each of Example 35 and 36 were added to separaterespective test tubes to which 1.8 mL of PBS solution was added, so thatthe total theoretical Drug 4 concentration was approximately 2000 μg/mLif all of Drug 4 were to dissolve completely; 3.6 mg each of Examples 37and 38 were added in separate respective test tubes to 1.8 mL of MFDsolution, to provide a total theoretical Drug 5 concentration ofapproximately 200 μg/mL if all of Drug 5 were to dissolve completely.Drug 4 concentration in the samples was determined as in Example 33.Drug 5 concentration in the samples was determined as in Example 34. Theresults are shown in Table 30. TABLE 30 Time [Drug 4] AUC Example (min)(μg/mL) (min*μg/mL) 35 0 0 0 4 771 1,500 10 773 6,200 20 781 13,900 40753 29,300 90 703 65,700 1200 540 755,500 36 0 0 0 4 420 1,000 10 4223,400 20 429 7,600 40 447 16,400 90 447 38,700 1200 319 463,900 37 0 0 04 121 200 10 113 900 20 111 7,100 40 111 4,300 90 120 10,100 1200 106135,500 38 0 0 0 4 429 900 10 347 3,200 20 280 6,300 40 229 11,400 90257 23,600 1200 164 237,200

[1367] The concentrations of Drug 4 and Drug 5 obtained in these sampleswere used to determine the values of C_(max90) and AUC₉₀. The resultsfor dispersion containg Drug 4 are shown below in Table 31, and fordispersions containing Drug 5 in Table 32. TABLE 31 Example C_(max90)AUC₉₀ 35 781 65,700 36 447 38,700 C11  131 10,300

[1368] TABLE 32 Example C_(max90) AUC₉₀ 37 121 10,100 38 429 23,600 C12  32  2,200

[1369] As can been seen from the data, the dispersions of examples 35and 36 provided superior concentration-enhancement relative to theControl C11 and Examples 37 and 38 provided superiorconcentration-enhancement relative to the Control C12.

[1370] The terms and expression which have been employed in theforegoing specification are used therein as terms of description and notof limitation, and there is no intention, in the use of such terms andexpressions, of excluding equivalents of the features shown anddescribed or portions thereof, it being recognized that the scope of theinvention is defined and limited only by the claims which follow.

What is claimed is:
 1. A pharmaceutical composition comprising a solidamorphous dispersion of an acid-sensitive drug and a neutral dispersionpolymer, wherein said composition provides improved chemical stabilityrelative to a control acidic dispersion comprised of an equivalentquantity of said drug and an acidic polymer.
 2. The composition of claim1 wherein said acid-sensitive drug has one or more functional groupsselected from the group consisting of sulfonyl ureas, hydroxamic acids,hydroxy amides, carbamates, acetals, hydroxy ureas, esters, and amides.3. The composition of claim 1 wherein said acid-sensitive drug whenpresent in a control acidic dispersion and stored for a period of sixmonths at 40° C. and 75% relative humidity has a degree of degradationof at least 0.01%.
 4. The composition of claim 3 wherein saidacid-sensitive drug in said control acidic dispersion has a degree ofdegradation of at least 0.1%.
 5. The composition of claim 1 wherein saiddrug comprises quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-3-fluorobenzyl-2(S),7-dihydroxy-7-methyl-octyl]amide;quinoxaline-2-carboxylic acid[1-benzyl-4-(4,4-difluoro-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide;quinoxaline-2-carboxylic acid[1-benzyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide;(+)-N-{3-[3-(4-fluorophenoxy)phenyl]-2-cyclopenten-1-yl}-N-hydroxyurea;omeprazole; etoposide; famotidine; erythromycin; quinapril;lansoprazole; or progabide.
 6. The composition of claim 1 wherein saiddrug in said composition has a relative degree of improvement inchemical stability of at least 1.25.
 7. The composition of claim 6wherein said relative degree of improvement is at least
 3. 8. Thecomposition of claim 7 wherein said relative degree of improvement is atleast
 10. 9. The composition of claim 4 wherein said drug in saidcomposition has a relative degree of improvement in chemical stabilityof at least 1.25 when stored at 40° C. and 75% relative humidity for aperiod of six months.
 10. The composition of claim 1 wherein saiddispersion polymer is ionizable.
 11. The composition of claim 1 whereinsaid dispersion polymer is non-ionizable.
 12. The composition of claim 1wherein said dispersion polymer is cellulosic.
 13. The composition ofclaim 12 wherein said dispersion polymer is selected from the groupconsisting of hydroxypropyl methyl cellulose acetate, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose,hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, andhydroxyethyl ethyl cellulose.
 14. The composition of claim 1 whereinsaid dispersion polymer is non-cellulosic.
 15. The composition of claim14 wherein said dispersion polymer is selected from the group consistingof vinyl polymers and copolymers having one or more substituentsselected from the group consisting of hydroxyl-containing repeat units,alkylacyloxy-containing repeat units, or cyclicamido-coritaining repeatunits; polyvinyl alcohols that have at least a portion of their repeatunits in the unhydrolyzed form; polyvinyl alcohol polyvinyl acetatecopolymers; polyethylene glycol, polyethylene glycol polypropyleneglycol copolymers, polyvinyl pyrrolidone; polyethylene polyvinyl alcoholcopolymers, and polyoxyethylene-polyoxypropylene block copolymers. 16.The composition of claim 15 wherein said dispersion polymer comprises avinyl copolymer having: (1) hydroxyl-containing repeat units; and (2)hydrophobic repeat units.
 17. The composition of claim 1 wherein saidacid-sensitive drug is also a low-solubility drug and said dispersionpolymer is concentration-enhancing.
 18. The composition of claim 17wherein said drug has a minimum solubility in aqueous solution in theabsence of said dispersion polymer of less than 1 mg/mL at any pH offrom about 1 to about
 8. 19. The composition of claim 18 wherein saiddrug has a minimum aqueous solubility of less than 0.01 mg/mL at any pHof from about 1 to about
 8. 20. The composition of claim 17 wherein saiddrug has a dose-to-aqueous-solubility ratio of at least 10 mL.
 21. Thecomposition of claim 17 wherein said dispersion polymer is present in anamount sufficient to provide a maximum concentration of saidacid-sensitive drug in a use environment that is at least 1.25-fold thatprovided by a second control composition comprising an equivalentquantity of said acid-sensitive drug and free from said dispersionpolymer.
 22. The composition of claim 21 wherein said maximumconcentration of said acid-sensitive drug in said use environment is atleast 2-fold that provided by said second control composition.
 23. Thecomposition of claim 17 wherein said dispersion polymer is present in asufficient amount so that said dispersion provides in a use environmentan area under the concentration versus time curve for any period of atleast 90 minutes between the time of introduction into the useenvironment and about 270 minutes following introduction to the useenvironment that is at least 1.25-fold that provided by a second controlcomposition comprising an equivalent quantity of said acid-sensitivedrug and free from said dispersion polymer.
 24. The composition of claim23 wherein said composition provides in a use environment an area underthe concentration versus time curve for any period of at least 90minutes between the time of introduction into the use environment andabout 270 minutes following introduction to the use environment that isat least 2-fold that of said second control composition.
 25. Thecomposition of claim 17 wherein said dispersion polymer is present in asufficient amount so that said dispersion provides a relativebioavailability that is at least 1.25 relative to a second controlcomposition comprising an equivalent quantity of said acid-sensitivedrug and free from said polymer.
 26. The composition of claim 25 whereinsaid relative bioavailability is at least 2 relative to said secondcontrol composition.
 27. The composition of claim 1 wherein said drug isalso base-sensitive and said dispersion polymer is non-ionizable. 28.The composition of claim 1 wherein said dispersion further comprises abuffer.
 29. The composition of claim 28 wherein said buffer is selectedfrom the group consisting of sodium acetate, ammonium acetate, sodiumcarbonate, sodium bicarbonate, disodium hydrogen phosphate and trisodiumphosphate.
 30. The composition of claim 28 wherein said buffer comprisesat least 10 wt % of said dispersion.
 31. The composition of claim 28wherein said dispersion has a pH from about 6 to about
 10. 32. Thecomposition of claim 1 further comprising a base and wherein saiddispersion has a pH of from about 6 to about
 10. 33. The composition ofclaim 1 wherein said acid-sensitive drug is a low-solubility drug andsaid composition further comprises a second polymer, said dispersion isfree from at least a portion of said second polymer, and said secondpolymer is concentration-enhancing.
 34. The composition of claim 33wherein said second polymer has at least one hydrophobic portion and atleast one hydrophilic portion.
 35. The composition of claim 33 whereinsaid second polymer is a cellulosic, ionizable polymer.
 36. Thecomposition of claim 35 wherein said second polymer is selected from thegroup consisting of hydroxypropyl methyl cellulose acetate succinate,hydroxypropyl methyl cellulose succinate, hydroxypropyl celluloseacetate succinate, hydroxyethyl methyl cellulose succinate, hydroxyethylcellulose acetate succinate, hydroxypropyl methyl cellulose phthalate,hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methylcellulose acetate phthalate, carboxyethyl cellulose, carboxymethylcellulose, cellulose acetate phthalate, methyl cellulose acetatephthalate, ethyl cellulose acetate phthalate, hydroxypropyl celluloseacetate phthalate, hydroxypropyl methyl cellulose acetate phthalate,hydroxypropyl cellulose acetate phthalate succinate, hydroxypropylmethyl cellulose acetate succinate phthalate, hydroxypropyl methylcellulose succinate phthalate, cellulose propionate phthalate,hydroxypropyl cellulose butyrate phthalate, cellulose acetatetrimellitate, methyl cellulose acetate trimellitate, ethyl celluloseacetate trimellitate, hydroxypropyl cellulose acetate trimellitate,hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate succinate, cellulose propionatetrimellitate, cellulose butyrate trimellitate, cellulose acetateterephthalate, cellulose acetate isophthalate, cellulose acetatepyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropylsalicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate,hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acidcellulose acetate, ethyl nicotinic acid cellulose acetate, and ethylpicolinic acid cellulose acetate.
 37. The composition of claim 35wherein said second polymer is selected from the group consisting ofhydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, and cellulose acetatetrimellitate.
 38. The composition of claim 33 wherein said secondpolymer is a non-ionizable cellulosic polymer.
 39. The composition ofclaim 38 wherein said second polymer is selected from the groupconsisting of hydroxypropyl methyl cellulose acetate, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose,hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, andhydroxyethyl ethyl cellulose.
 40. The composition of claim 33 whereinsaid polymer is an ionizable, non-cellulosic polymer.
 41. Thecomposition of claim 40 wherein said polymer is selected from the groupconsisting of carboxylic acid functionalized polymethacrylates,carboxylic acid functionalized polyacrylates, amine-functionalizedpolyacrylates, amine-fuctinoalized polymethacrylates, proteins, andcarboxylic acid functionalized starches.
 42. The composition of claim 33wherein said second polymer is a non-ionizable, non-cellulosic polymer.43. The composition of claim 42 wherein said second polymer is selectedfrom the group consisting of vinyl polymers and copolymers having one ormore substituents selected from the group consisting ofhydroxyl-containing repeat units, alkylacyloxy-containing repeat units,or cyclicamido-containing repeat units; polyvinyl alcohols that have atleast a portion of their repeat units in the unhydrolyzed form;polyvinyl alcohol polyvinyl acetate copolymers; polyethylene glycol,polyethylene glycol polypropylene glycol copolymers, polyvinylpyrrolidone polyethylene polyvinyl alcohol copolymers, andpolyoxyethylene-polyoxypropylene block copolymers.
 44. The compositionof claim 43 wherein said second polymer comprises a vinyl copolymerhaving: (1) hydroxyl-containing repeat units; and (2) hydrophobic repeatunits.
 45. The composition of claim 33 wherein said drug in saidcomposition has a relative degree of improvement in chemical stabilityof at least 1.25.
 46. The composition of claim 33 wherein said relativedegree of improvement is at least
 3. 47. The composition of claim 33wherein said dispersion is mixed with said second polymer.
 48. Thecomposition of claim 33 wherein said dispersion and said second polymeroccupy separate regions of said composition.
 49. The composition ofclaim 33 wherein said second polymer is present in an amount sufficientto provide a maximum concentration of said acid-sensitive drug in a useenvironment that is at least 1.25-fold that of a control compositioncomprising an equivalent quantity of said dispersion and free from saidsecond polymer.
 50. The composition of claim 49 wherein said maximumconcentration of said acid-sensitive drug in said use environment is atleast 2-fold that of said control composition.
 51. The composition ofclaim 33 wherein said second polymer is present in a sufficient amountso that said composition provides in a use environment an area under theconcentration versus time curve for any period of at least 90 minutesbetween the time of introduction into the use environment and about 270minutes following introduction to the use environment that is at least1.25-fold that of a control composition comprising an equivalentquantity of said dispersion and free from said second polymer.
 52. Thecomposition of claim 51 wherein said composition provides in a useenvironment an area under the concentration versus time curve for anyperiod of at least 90 minutes between the time of introduction into theuse environment and about 270 minutes following introduction to the useenvironment that is at least 2-fold that of said control composition.53. The composition of claim 33 wherein said second polymer is presentin a sufficient amount so that said composition provides a relativebioavailability that is at least 1.25 relative to a control compositioncomprising an equivalent quantity of said dispersion and free from saidsecond polymer.
 54. The composition of claim 53 wherein said relativebioavailability is at least 2 relative to said control composition. 55.A method for treating a condition in an animal comprising byadministering to an animal in need of such treatment a therapeuticamount of a composition of claim
 1. 56. A method of administering apharmaceutical composition comprising co-administering to a patient: (a)a solid amorphous dispersion comprised of an acid-sensitive drug and aneutral polymer; and (b) a second polymer, wherein said dispersion issubstantially free from said second polymer and said second polymer isconcentration-enhancing.
 57. The method of claim 56 wherein said secondpolymer is cellulosic.
 58. The method of claim 56 wherein said secondpolymer is selected from the group consisting of hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, methyl cellulose acetate phthalate,cellulose acetate trimellitate, hydroxypropyl cellulose acetatephthalate, cellulose acetate terephthalate and cellulose acetateisophthalate.
 59. The method of claim 56 wherein said dispersion isadministered separately from said second polymer.
 60. The method ofclaim 56 wherein said dispersion and said second polymer areadministered at about the same time.
 61. A pharmaceutical compositioncomprising a solid amorphous dispersion of a low-solubility drug and aneutral dispersion polymer, wherein said neutral dispersion polymercomprises a vinyl copolymer having hydrophilic hydroxyl-containingrepeat units and hydrophobic repeat units.
 62. The composition of claim61 wherein said hydrophobic repeat units include ester-linked alkylateor arylate substituents.
 63. The composition of claim 62 wherein saidhydrophobic repeat unit is an alkylate selected from the groupconsisting of acetate, propionate, and butyrate.
 64. The composition ofclaim 63 wherein said alkylate is acetate.
 65. The composition of claim61 wherein said hydroxyl-containing repeat unit is vinyl alcohol. 66.The composition of claim 61 wherein said dispersion polymer is a vinylalcohol/vinyl acetate copolymer.
 67. The composition of claim 66 whereinfrom 0.5 to 30% of the repeat units of said polymer are vinyl acetate.68. The composition of claim 61 wherein said hydrophobic repeat unitscomprise the acetylated form of the hydroxyl-containing repeat units.69. The composition of claim 68 wherein said acetylated form of thehydroxyl-containing repeat units comprise 0.5 to 30% of the repeat unitsof the polymer.
 70. A pharmaceutical composition comprising a solidamorphous dispersion comprising a low-solubility drug, a neutraldispersion polymer, and an excipient selected from the group consistingof a base and a buffer.
 71. The composition of claim 70 wherein saidneutral dispersion polymer is concentration enhancing.
 72. Thecomposition of claim 71 wherein said neutral dispersion polymer ispresent in an amount sufficient to provide a maximum concentration ofsaid low-solubilty drug in a use environment that is at least 1.25-foldthat provided by a second control composition comprising an equivalentquantity of said low-solubility drug and free from aconcentration-enhancing polymer.
 73. The composition of claim 71 whereinsaid neutral dispersion polymer is present in a sufficient amount sothat said composition, when introduced to a use environment, provides anarea under the concentration-versus time curve for any period of atleast 90 minutes between the time of introduction to the use environmentand about 270 minutes following introduction to the use environment thatis at least 1.25-fold that of a second control composition comprising anequivalent quantity of said low-solubility drug and free from aconcentration-enhancing polymer.
 74. The composition of claim 71 whereinsaid neutral dispersion polymer is present in a sufficient amount sothat said composition provides a relative bioavailability that is atleast 1.25 relative to a second control composition comprising anequivalent quantity of said low-solubility drug and free from aconcentration-enhancing polymer.
 75. The composition of claim 70 whereinsaid drug in said composition has a relative degree of improvement inchemical stability of at least 1.25.
 76. The composition of claim 70wherein said composition provides improved chemical stability relativeto a control composition, wherein said control comprises an equivalentquantity of a dispersion of said drug and said neutral dispersionpolymer but free from said base and said buffer.
 77. The composition ofany of claims 1, 61 or 70, wherein the drug comprises a CETP inhibitoror a CCR1 inhibitor.
 78. The composition of any of claims 1, 61 or 70,wherein the drug comprises [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester; [2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester; or [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl0-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.
 79. The composition of claim 61 or 70, wherein thedrug comprises quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-3-fluorobenzyl-2(S),7-dihydroxy-7-methyl-octyl]amide;quinoxaline-2-carboxylic acid[1-benzyl-4-(4,4-difluoro-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide;or quinoxaline-2-carboxylic acid[1-benzyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide.